STAMBP Data Analysis

HGNC Gene Name: STAM binding protein
HGNC Gene Symbol: STAMBP
Identifiers: hgnc:16950 NCBIGene:10617 uniprot:O95630
Orthologs: mgi:1917777 rgd:619963
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for STAMBP
Number of Papers: 75 retrieved on 2023-02-19

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol	Name	DepMap Correlation	Evidence	CCLE Correlation	CCLE Z-score	CCLE p-value (adj)
USP8	ubiquitin specific peptidase 8	0.377	Pathway Commons INDRA (6) Reactome (3)	0.32	1.68	2.51e-09
VPS36	vacuolar protein sorting 36 homolog	0.33		0.29	1.51	1.14e-07
PTPN23	protein tyrosine phosphatase non-receptor type 23	0.314		0.25	1.27	9.45e-06
IST1	IST1 factor associated with ESCRT-III	0.247	INDRA (1)	0.43	2.27	1.64e-16
EIF3M	eukaryotic translation initiation factor 3 subunit M	-0.23	Reactome (1)	0.03	0.06	7.20e-01
GRK2	G protein-coupled receptor kinase 2	0.217
DOK1	docking protein 1	0.195		0.32	1.70	4.80e-08

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with STAMBPusing the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier	GO Name	GO Type	p-value	p-value (adj.)	q-value
GO:0007032	endosome organization	Biological Process	2.40e-06	4.97e-04	2.48e-04
GO:0043162	ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	Biological Process	2.69e-05	5.56e-03	1.39e-03
GO:0036257	multivesicular body organization	Biological Process	5.40e-05	1.12e-02	1.86e-03
GO:0016050	vesicle organization	Biological Process	1.60e-04	3.30e-02	4.12e-03

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out STAMBP using CRISPR-Cas9.

Knockout Differential Expression

Symbol	Name	log₂-fold-change	p-value	p-value (adj.)
STAMBP	STAM binding protein	-1.17e+00	3.97e-09	8.75e-05

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to STAMBP from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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STAMBP deubiquitinates NLRP7. 7 / 7

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STAMBP is sufficient to deubiquitinate NALP7 and is necessary to stabilize NALP7 protein in cells exposed to LPS or Pam3CSK4.

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We next tested inhibition of STAMBP DUB activity specific to Ub-NALP7; here inclusion of BC-1471 blocked STAMBP mediated deubiquitination of Ub-NALP7 in vitro in a concentration dependent manner (XREF_FIG), where BC-1471 performed comparably to the broad-spectrum metalloprotease DUB inhibitor 1,10-phenanthroline.

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Bednash et al.75 showed that the DUB STAMPBP (or AMSH) deubiquitinates NLRP7 rescuing this receptor from progressing to lysosome degradation and making it available for the formation of an active inflammasome.NLRC4 inflammasome activation can also be controlled by ubiquitination, although very little is known about how this occurs.

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This finding supports that STAMBP is sufficient to directly deubiquitinate NALP7.

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BC-1471 (43) was discovered as a specific STAMBP inhibitor (IC 50 = 0.33 muM) that selectively blocked deubiquitination of Ub-NALP7 by recombinant STAMBP [XREF_BIBR] but did not significantly inhibit the activity of a panel of 38 different DUBs at the concentration tested.

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Since STAMBP is known to function as a DUB, we developed a cell-free DUB assay to test STAMBP deubiquitination of NALP7.

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STAMBP deubiquitinates EGFR. 6 / 6

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AMSH can deubiquitinate EGFR and prompt recycling to the plasma membrane [XREF_BIBR], whilst USP8 is required for the degradation of EGFR in the lysosome [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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13 This implies that AMSH is able to completely deubiquitinate EGFR, since monoubiquitinated EGFR can still be targeted to lysosome.

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In support of this notion, we are able to show that EGFR, immunoprecipitated from EGF stimulated Her14 cells, can be deubiquitinated by AMSH in vitro.

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AMSH was shown to deubiquitylate in vitro EGFR immunoprecipitated from EGF stimulated cells [XREF_BIBR], and siRNA knockdown of AMSH resulted in accelerated EGFR degradation in HeLa cells, which suggests that AMSH dependent deubiquitylation of EGFR counteracts Cbl dependent ubiquitylation of the receptor [XREF_BIBR].

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STAMBP may deubiquitinate EGFR by localizing in early endosomes and increase EGFR membrane localization in LUAD cells.

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AMSH (associated molecule with the SH3 domain of STAM) expression is elevated in many cancers and is capable of hydrolyzing K63-linked Ub chains from epidermal growth factor receptor (EGFR) recycling it to the plasma membrane

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STAMBP deubiquitinates EGFR phosphorylated on Y1172, Y1110, K867, K754, K929, Y1092, Y1016, K716, Y1197, K970, and Y1069 on K737. 2 / 2

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STAMBP deubiquitinates EGFR phosphorylated on Y1172, Y1110, K867, K737, K754, K929, Y1092, Y1016, Y1197, K970, and Y1069 on K716. 2 / 2

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STAMBP deubiquitinates EGFR phosphorylated on Y1172, Y1110, K867, K737, K929, Y1092, Y1016, K716, Y1197, K970, and Y1069 on K754. 2 / 2

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STAMBP deubiquitinates EGFR phosphorylated on Y1172, Y1110, K867, K737, K754, Y1092, Y1016, K716, Y1197, K970, and Y1069 on K929. 2 / 2

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STAMBP deubiquitinates EGFR phosphorylated on Y1172, Y1110, K867, K737, K754, K929, Y1092, Y1016, K716, Y1197, and Y1069 on K970. 2 / 2

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STAMBP deubiquitinates EGFR phosphorylated on Y1172, Y1110, K737, K754, K929, Y1092, Y1016, K716, Y1197, K970, and Y1069 on K867. 2 / 2

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STAMBP leads to the deubiquitination of F2RL1. 2 / 2

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Expression of the catalytically inactive mutants, AMSH(D348A) and UBPY(C786S), caused an increase in PAR(2) ubiquitination and trapped the receptor in early endosomes, thereby preventing lysosomal trafficking and degradation.

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USP8 and AMSH mediate deubiquitination of PAR2 and its sorting from endosomes to lysosomes [XREF_BIBR].

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STAMBP deubiquitinates v-SNARE. 1 / 1

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XREF_BIBR; XREF_BIBR; XREF_BIBR; XREF_BIBR During mitosis, AMSH deubiquitinates v-SNARE and VAMP8 in an ESCRT dependent manner, while also being present in the early phases of cytokinesis, both implicating a potential role of AMSH as a regulator of proliferation and survival.

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STAMBP leads to the deubiquitination of ART4. 1 / 1

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In addition, Art4-AMSH exhibited an intermediate reduction in ubp2Delta ubp15Delta cells (XREF_FIG, lanes 7 and 8, and C), suggesting partial inhibition of Art4 hyperubiquitination by AMSH.

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STAMBP leads to the deubiquitination of EPS15. 1 / 1

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This means that RNF11 could promote the internalisation and degradation of the EGFR via two distinct mechanisms, either by degradation of AMSH and/or mediating the mono-ubiquitination of EPS-15.

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STAMBP deubiquitinates GJA1. 1 / 1

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AMSH-mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions

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STAMBP affects MC4R

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STAMBP activates MC4R. 10 / 29

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In summary, activation of the POMC-expressing neurons in the hypothalamic arcuate nucleus triggers the release of α-MSH, which activates MC4R at the paraventricular nucleus, leading to suppressed food intake and increased energy expenditure.

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The MC4R is activated principally by α-MSH, leading to neuronal depolarization and action potential firing, while AgRP acts as an antagonist or biased agonist promoting neuronal hyperpolarization (see below).

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Α-MSH activates MC3-R and MC4-R equally but γ 2 -MSH has a higher affinity for MC3-R [1,2] .

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In vitro , EC 50 for α-MSH activation of MC4R(I316S) and MC4R(I317T) are similar to the wild-type MC4R, however maximum receptor activity is reduced xref – xref .

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On the other hand, α-MSH-induced MC4R activation stimulates the pertussis toxin (PTx)-sensitive GTPγS binding in a hypothalamic cell line (GT1-7 cells) suggesting that MC4R is also able to couple to G[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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ACTH can activate all five receptor subtypes; of the melanocortins, only ACTH activates MC2R; ACTH as well as α-MSH, β-MSH and γ-MSH activate MC1R, MC3R, MC4R and MC5R, although with varying affinities.

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Activation of the melanocortin 4 receptor (MC4R) by α-MSH is also thought to stimulate TRH gene transcription ( xref ).

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Α-MSH binds and activates melanocortin 4 receptor (MC4R), resulting in an increase in cAMP, inducing the sensation of satiety.

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The mechanism of action of α-MSH-reactive IgG may include activation of MC4R by the immune complexes with α-MSH, which deregulates feeding behavior and emotions [ xref ].

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ACTH (1–39) or α-MSH can activate MC1R, MC3R, MC4R, and MC5R ( xref ), but MC2R can only be activated by ACTH and not by α-MSH or other analogs ( xref ).

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TRH affects STAMBP

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TRH activates STAMBP. 10 / 20

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However, the present study indicates that SRIF does not modulate TRH induced aMSH release by frog neurointermediate lobes.

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Our data show that PGE1 potentiates the release of a-MSH induced by TRH.

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Since in our model indomethacin does not blunt the release of a-MSH induced by TRH, the present data show that endogenous prostaglandins are not involved in the response of intermediate lobe pituitary[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Several recent studies have demonstrated that in the frog, the tripeptide pGlu-His-Pro-NH2 (mammalian TRH) specifically stimulates a-MSH release by NIL in vitro (Vaudry et al., 1977; Tonon et al., 198[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Our results suggest that extracellular prostaglandins may modulate the release of a-MSH induced by TRH which indicate that prostaglandins act on mammalian thyrotroph and amphibian melanotroph receptor[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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As shown in Fig. 3, SRIF (10 -6 M) was unable to alter either spontaneous oMSH release or TRH induced a-MSH secretion by the NIL.

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At doses of 10-8 and 10-6 M, synthetic somatostatin did not modify TRH induced a-MSH secretion.

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For doses ranging from 10 -9 to 10-6M, VIP did not significantly alter a-MSH secretion whereas TRH induced a marked increase in (x-MSH release with half-maximum stimulation (EDSO) at 1.2 x 10-8M Table[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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2) Infusion of indomethacin alone (5 x 10-6M) did not alter the spontaneous release of a-MSH; 3) Association of indomethacin and TRH did not modify TRH stimulated a-MSH release; 4) Although a-MSH rele[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In addition, prolonged infusion of T, in vitro did not alter spontaneous and TRH induced a-MSH release.

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STAMBP affects EGFR

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STAMBP activates EGFR.

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STAMBP activates EGFR. 8 / 10

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13 Although AMSH depletion does not impair epidermal growth factor receptor degradation, 14,15 inhibition of its recruitment to endosomes by ESCRT-III charged MVB protein (CHMP) 3 impairs epidermal gr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Mechanistically, increased STAMBP expression promoted the stabilization of Epidermal growth factor receptor (EGFR), whereas STAMBP knockdown induced the degradation of EGFR.

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Its homologue STAMBP (or AMSH) is known to participate in endosomal sorting of receptors and membrane proteins [XREF_BIBR], e.g., STAMBP knockdown enhancing EGFR degradation.

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In other studies, both AMSH XREF_BIBR, XREF_BIBR and UBPY XREF_BIBR, XREF_BIBR, XREF_BIBR have been reported to increase EGFR down-regulation.

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Nevertheless, both AMSH [31, 34, 35] and UBPY [32, 33, 36-38] have been reported to increase EGFR down-regulation.

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Consistently, knockdown of endogenous AMSH or overexpression of catalytically inactive AMSH mutants has been shown to promote the lysosomal degradation of epidermal growth factor receptor (EGFR) as well as other cell surface receptors [XREF_BIBR - XREF_BIBR].

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Similarly, endosomal deubiquitinase AMSH (Associated Molecule with the SH3-domain of STAM) has been shown to antagonize the ubiquitin dependent lysosomal degradation of EGFR by trimming the K63 linked ubiquitin chains [XREF_BIBR] while other studies have shown this DUB to be required for MVB dependent EGFR degradation [XREF_BIBR, XREF_BIBR].

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STAMBP promotes lung adenocarcinoma metastasis by regulating the EGFR and MAPK signaling pathway.

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STAMBP inhibits EGFR.

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STAMBP inhibits EGFR. 5 / 8

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Short interfering RNA (siRNA) knockdown of AMSH accelerates EGFR down-regulation.

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Depletion of AMSH, which alters the balance of E3 ligase and DUB activity in the endosomal system, enhances the degradation of EGFR, presumably by inhibiting the removal of ubiquitin from EGFR and thereby preventing its ability to recycle.

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In contrast, EGF-R internalization is inhibited by AMSH protein.

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Conversely, AMSH negatively regulates EGFR down-regulation and is proposed to recycle the EGFR at the sorting endosome.

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Inhibition of AMSH accelerates EGFR down-regulation suggesting a role in antagonizing ubiquitin dependent sorting of cargo to the lysosome.

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STAMBP affects MC1R

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STAMBP activates MC1R. 10 / 16

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Activation of MC1R by α-MSH or ACTH increases cAMP synthesis which indirectly induces a switch from the production of pheomelanin to eumelanin synthesis [ xref ] ( xref ).

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Both mc1r and mc4r are activated by α-MSH and are involved in the control of the pigmentation and the modulation of food intake, respectively xref xref xref .

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The activation of MC1R by its ligand α-MSH or adrenocorticotropic hormone (ACTH) leads to an increase in adenylyl cyclase, which in turn upregulates intracellular cAMP levels [ xref , xref ].

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The MC1R is activated by α-MSH and antagonized by agouti signaling protein (ASIP).

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In macrophages, α-MSH activates MC1R and inhibits lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) activation xref .

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In both cases, knock-down of AgRP2 xref would be expected to increase MC1R activation by α-MSH, leading to the dispersion of melanosomes and decreased camouflage capability.

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The activity of MITF is positively regulated by signaling downstream of the MC1R, which are in turn activated by α-MSH produced by UV-irradiated keratinocytes xref .

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Additionally, activation of MC1R by α-MSH regulates intracellular redox status by up regulating the expression of antioxidant genes, including heme oxygenase-1 (HO-1), ferritin, and peroxiredoxin-1 ( xref ; xref ).

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MC1R activation by the α-MSH produced in keratinocytes results in stimulation of synthesis of photoprotective eumelanin (brown-black pigment) in melanocytes.

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STAMBP affects 3',5'-cyclic AMP

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STAMBP activates 3',5'-cyclic AMP.

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STAMBP activates 3',5'-cyclic AMP. 10 / 14

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It has been reported that MITF downregulation is related to the suppression of the cAMP dependent melanogenic pathway stimulated by a-MSH in melanoma cells.

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In E15-16 rat neuronal cortical cultures ACTH (1-24), ACTH (1-17), a-MSH,, Q-MSH, ACTH (1-10), and ACTH (410) stimulate cAMP production fourfold.

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Even after l h preincubation with a-MSH, subsequent washing and reintroduction of a-MSH or ACTH produces some further stimulation of cAMP accumulation.

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The incubation of a-MSH with tissues previously enriched with TBG induces a higher increase in the content of cAMP than that induced by a-MSH alone.

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The second effect is a synergic action forming cAMP induced by the aMSH.

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However, because a-MSH stimulates to a greater extent, the actual amount of cAMP in the cells is still greater in the cells treated with a-MSH.

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Org2766 and a-MSH increased cyclic AMP content of Schwann cells but neither stimulated DNA synthesis when applied alone.

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On other hand, in an accompanying article we describe the synergic action of gangliosides on the cyclic AMP release induced by a-MSH in rat brain slices (18).

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A-MSH in the presence of bromocriptine produced an increase in cAMP (a similar effect was obtained when the peptide was alone).

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DISCUSSION We have examined the effects of a-MSH on intracellular cAMP levels in thin slices containing CP and Acc and we found that a-MSH stimulated cAMP production in a dose dependent fashion.

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STAMBP inhibits 3',5'-cyclic AMP.

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STAMBP inhibits 3',5'-cyclic AMP. 1 / 1

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Another possible explanation for this phenomenon could be that in the presence of DA the insertion of a-MSH in the membrane nonspecifically inhibits cAMP accumulation induced by D, activation.

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C1QL1 affects STAMBP

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C1QL1 activates STAMBP.

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C1QL1 activates STAMBP. 7 / 7

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These observations are in good agreement with the presence of specific [' ^ Ijiodosulpiride binding sites in the IL at E20 (Sales et al., 1989), and with the DA inhibi- tion of the CRF stimulated aMSH[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The ability of CRF to stimulate release of ACTH and a-MSH in vivo coupled with the knowledge of the potent antipyretic effect of these peptides leads us to speculate that a central CRF- ACTH/~-MSH cas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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After a 6-h incubation with pars intermedia cells in culture, ovine CRF (300 nM) stimulates a-MSH release at an ED5o value of 1 nM.

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Proulx-Ferland L., Labrie F., Dumont D., CJ., Coy D. H. and Sueiras-Diaz J. : CRF stimulates a-MSH secretion from the intermediate lobe of the rat pituitary.

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Meunier H., Lefre G., Dumont D. and Labrie F. : CRF stimulates a-MSH secretion and cyclic AMP ac- cumulation in rat pars intermedia cells.

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Moreover, CRF causes a rapid stimulation of a-MSH release and cyclic AMP accumulation in rat pars intermedia cells in culture, thus demon- strating a direct action of the peptide on the inter- mediate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Proulx-Ferland L., Labrie F., Dumont D., CJ., Coy D. H. and Sueiras-Dias J. : CRF stimulates secretion of a-MSH from the rat pituitary.

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C1QL1 inhibits STAMBP.

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C1QL1 inhibits STAMBP. 3 / 3

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As observed previously for the stimulatory effect of adrenergic agents on a-MFSH release [14-16], the dopaminergic agonist, CB-154, causes an almost complete inhibition of CRF induced a-MSH release.

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It can also be seen that preincubation with the potent glucocorti- coid dexamethasone, under conditions which lead to an almost complete inhibition of ACTH secretion in corticotrophs of the anterior p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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As observed previously for the stimulatory effect of adrenergic agents on cyclic AMP accumulation and a-MSH release (11, 12, 19, 20), the dopaminergic agonist CB-154 leads to an almost complete inhibi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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C1QL1 increases the amount of STAMBP.

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C1QL1 increases the amount of STAMBP. 1 / 1

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Since CRF increases the levels of the antipyretic peptides ACTH and a-MSH, we injected it both centrally and periph- erally to learn whether it too reduces fever.

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STAMBP affects cre

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STAMBP activates cre. 10 / 10

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As shown in xref , substantial inhibition of Rap-1a protein expression (~50%) was obtained, accompanied by significant inhibition of α-MSH-induced CRE activation (~30%).

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Next, we transfected the CRE reporter into GT1-7 cells and analysed the effects of PKA and EPAC-1/2 inhibitors on α-MSH-induced CRE activation ( xref , and xref ).

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Thus the involvement of EPACs in α-MSH-induced CRE activation is not a HEK-293 cell specific phenomenon, but rather a common feature of the MC4R. In contrast to HEK-293 cells, the EPAC-2 specific inhibitor ESI-05 also blocked α-MSH-induced CRE activation in GT1-7 cells underscoring cell-type specific roles of EPAC-1 and -2 in this process.

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As shown in xref ( xref ), both EPAC-1/2 inhibitors blocked ~80% of α-MSH-induced CRE activation in mHypoA-2/10-CRE cells, in accord with our data obtained in HEK-293 and GT1-7 cells.

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EPAC requirement for α-MSH-induced CRE activation is not restricted to the MC4R subtype.

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In contrast, both EPAC-1/2 inhibitors blunted α-MSH-induced CRE activation, compatible with the notion that EPAC-1/2 activity is required.

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To clarify this issue, we employed the B16F10 mouse melanoma cell line endogenously expressing MC1R and investigated the contribution of PKA and EPAC to α-MSH-induced CRE activation ( xref ).

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In contrast to HEK-293 and GT1-7 cells, PKA blockers significantly inhibited α-MSH-induced CRE activation in mHypoA-2/10-CRE cells.

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As shown in xref , ERK-1/2 inhibition significantly decreased α-MSH-induced CRE activation in both cell lines, lending further credence to the concept that MC4R-induced CRE activation requires EPAC and ERK-1/2 activity.

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Pivotal role of EPACs for α-MSH-induced CRE activation.

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STAMBP affects ATF2

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STAMBP activates ATF2. 10 / 10

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Next, we transfected the CRE reporter into GT1-7 cells and analysed the effects of PKA and EPAC-1/2 inhibitors on α-MSH-induced CRE activation ( xref , and xref ).

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In contrast, both EPAC-1/2 inhibitors blunted α-MSH-induced CRE activation, compatible with the notion that EPAC-1/2 activity is required.

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As shown in xref , substantial inhibition of Rap-1a protein expression (~50%) was obtained, accompanied by significant inhibition of α-MSH-induced CRE activation (~30%).

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In contrast to HEK-293 and GT1-7 cells, PKA blockers significantly inhibited α-MSH-induced CRE activation in mHypoA-2/10-CRE cells.

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To clarify this issue, we employed the B16F10 mouse melanoma cell line endogenously expressing MC1R and investigated the contribution of PKA and EPAC to α-MSH-induced CRE activation ( xref ).

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As shown in xref ( xref ), both EPAC-1/2 inhibitors blocked ~80% of α-MSH-induced CRE activation in mHypoA-2/10-CRE cells, in accord with our data obtained in HEK-293 and GT1-7 cells.

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EPAC requirement for α-MSH-induced CRE activation is not restricted to the MC4R subtype.

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Pivotal role of EPACs for α-MSH-induced CRE activation.

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STAMBP affects ERK

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STAMBP activates ERK. 9 / 9

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The characterization of the second clone involved the study of ERK1/2 activation by α-MSH in order to guarantee that observations were not clone specific.

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In pEGFPN1-transfected cells, α-MSH did not activate ERK1/2 (A, lanes GFP).

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For instance, our results demonstrate that the late activation of ERK1/2 by α-MSH is also β-arrestins dependent.

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Since MC5R activation was reported to promote binding of β-arrestin 2 ( Cai et al., 2006 ), we tested whether β-arrestins 1/2 are involved in α-MSH-induced ERK1/2 activation.

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In GT1-7 cells, ERK1/2 activation through MC4R induced by α-MSH is only PKA-dependent [ xref ].

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Tyrosinase (TYR) is a key enzyme that regulates melanin synthesis, xref which is regulated by a microphthalmia-associated transcription factor (MITF). xref It is reported that Erk1/2 activation can phosphorylate MITF at Ser73 and 409 sites, leading to a temporary increase in the trans-activation activity and subsequent degradation of MITF. xref As α-MSH can activate the ERK1/2 signaling via binding to MC1R, xref , xref we conjecture that ERK1/2/MITF/TYR signaling may be involved in α-MSH-PE38KDEL-mediated apoptosis of melanoma cells.

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Small molecule inhibitors of EGFR and MAPK signaling pathway may block STAMBP induced cell mobility and invasion as well as ERK activation in cells.

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We found that α-MSH induced significant activation of ERK1/2 in the WT hMC3R (Fig. xref ), consistent with previous studies when the WT MC3R was stimulated with either NDP-MSH or D-Trp 8 -γ-MSH as well as in mouse dorsal medial nucleus and ventromedial nucleus xref , xref , xref , although not consistent with another report xref .

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As shown in A, the inhibition of adenylyl cyclase has no effect on α-MSH-induced ERK1/2 activation.

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STAMBP bound to MC1R activates ERK. 1 / 1

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In mouse melanocytes, ERK activation by αMSH binding to Mc1r depends on cAMP, and melanocytes are considered a paradigm for cAMP-dependent ERK activation.

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STAM affects STAMBP

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STAM activates STAMBP.

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STAM activates STAMBP. 5 / 6

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In addition, STAM directed AMSH cleavage toward the distal isopeptide bond in tri-ubiquitin chains.

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In addition, we observed inhibition of STAM1-activated full-length STAMBP by both UbVSP.

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We propose that STAM fulfills an adaptor function for AMSH and that there might be a correspondingly diverse set of DUB and adaptor combinations.The ability of STAM to directly stimulate AMSH activity[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Next, we compared the K63-diUb (FRET) cleavage inhibition by the UbVs with STAMBPJAMM to the inhibition of full-length STAMBP activated by STAM protein and full-length STAMBPL1.

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It has been reported that pre-incubation with STAM stimulates AMSH 's DUB activity on tetra-Ubs, which supports our data strongly [25].

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STAM inhibits STAMBP.

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STAM inhibits STAMBP. 4 / 4

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In addition, we observed inhibition of STAM1-activated full-length STAMBP by both UbVSP.1 and UbVSP.3 in this chain cleavage assay (Fig. S2C).

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In addition, we observed inhibition of STAM1-activated full-length STAMBP by both UbV SP.1 and UbV SP.3 in this chain cleavage assay (Fig. S2C) .

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Next, we compared the K63-diUb (FRET) cleavage inhibition by the UbVs with STAMBP JAMM to the inhibition of fulllength STAMBP activated by STAM protein and full-length STAMBPL1.

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Next, we compared the K63-diUb (FRET) cleavage inhibition by the UbVs with STAMBPJAMM to the inhibition of full-length STAMBP activated by STAM protein and full-length STAMBPL1.

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PMCH affects STAMBP

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PMCH inhibits STAMBP.

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PMCH inhibits STAMBP. 6 / 6

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In teleosts a neurohormone, melanin- concentrating hormone (MCH), antagonizes a-MSH in this respect (5).

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MCH antagonizes the stimulatory effects of a-MSH on the response of rats to auditory stimuli (23) and on grooming (8), and has the opposite effect of a-MSH on extinction of passive avoidance (22).

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No effect was noted after injection of MCH, but prior administration of MCH reduced the activity of a-MSH.

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MCH administered alone had no effect on this parameter, but prevented the effect of a-MSH when given 30 min earlier.

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At concentrations below 1 pM, synthetic MCH caused a concentration dependent inhibition of a-MSH release.

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Immunoneutralization of MCH in NILs in vitro showed that in tilapia endogenous MCH inhibits a-MSH release from the melanotropes and that this inhibitory effect persists in vitro as long as 18 h, becau[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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PMCH activates STAMBP.

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PMCH activates STAMBP. 4 / 4

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A high concentration of MCH (10 pM) substantially increased the release of a-MSH.

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trations above 1 pM of MCH stimulated a-MSH release.

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Further evidence in support of a stimulatory action of high concentrations of MCH was provided by the observation that the MCH analogue MCH (217) at 10 and 35 p l' enhanced a-MSH release as well.

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High concentrations of MCH (10 pAf) and MCH (2-17) (10 and 35 MM) significantly increased a-MSH release.

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Dopamine affects STAMBP

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Dopamine inhibits STAMBP.

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Dopamine inhibits STAMBP. 8 / 8

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Dopamine inhibition of a-MSH secretion is, achieved via a D2 like receptor coupled to a G protein and inhibiting adenylyl cyclase (8,15).

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Thus, the lowest levels of the cyclic nucleotide obtained with the peptide + DZ or B could probably be attributed to : a) the lesser amount of DA released when exogenous a-MSH is applied in the presen[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The effect of dopamine, previously observed to strongly inhibit hypoph- yseal a-MSH release [4, 22, 23], was also studied.

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Both baclofen and dopamine appeared to inhibit a-MSH secretion but strongly stimulated the release of cAMP.

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Concerning our studies in the absence of IBMX, we have to consider how baclofen and dopamine inhibited a-MSH release.

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We have also studied the effect of two dopamine agonists, apomorphine and bromocryptine, that are known to inhibit a-MSH secretion in the rat [11].

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Moreover, although bromocryptine, a dopamine agonist that inhibits a-MSH release from the pituitary reduced the darkness of the coat that grew after plucking the reduction in coat darkening was unrela[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In the present study, the inhibitory action of dopamine on a-MSH release in frogs was confirmed by the observation that the dopamine agonist 2a-bromoergocryptine inhibited a-MSH secretion.

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Dopamine activates STAMBP.

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Dopamine activates STAMBP. 1 / 1

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Using this method to follow cAMP dynamics of melanotrope cells in the neurointermediate pituitary lobe of the amphibian Xe ^ opM ^ / ae ' vM we show that the a-MSH secreto- inhibitors baclofen (GABAg [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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STAMBP affects inflammatory response

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STAMBP inhibits inflammatory response. 8 / 8

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It has not been established which receptors mediate the central α-MSH-induced inhibition of peripheral inflammation.

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Α-MSH inhibits inflammation in experimental autoimmune uveitis (EAU), induces CD25+ regulatory CD4+ T-cells [ xref , xref , xref ] and regulates ubiquitination in T cells as well [ xref ].

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A-MSH has been shown to inhibit the acute inflammation induced in mice by IL-1, IL-6 and TNF-a [41].

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The neuropeptide aMSH, a potent modulator of fever and inflammation, can act at the central level to inhibit inflammation in peripheral tissues (7).

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Of note, inhibition of allergic airways inflammation in mice by α-MSH, is mediated via IL-10 production, because IL-10 knockout mice are resistant to α-MSH treatment ( Raap et al , 2003 ).

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Α-MSH can also inhibit the local inflammatory response by inhibiting neutrophil chemotaxis ( xref , xref ).

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We conclude that a-MSH treatment suppressed inflammation and was associated with decreased expression of Th1 cytokines.

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The α-MSH peptides inhibit acute inflammation induced in mice by rIL-1β ( Hiltz et al., 1992 ).

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STAMBP affects NLRP7

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STAMBP increases the amount of NLRP7.

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STAMBP increases the amount of NLRP7. 3 / 3

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In the current study, STAMBP silencing decreases NALP7 levels constitutively, but has a more robust effect when cells are exposed to TLR agonists as a stimulus.

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A small-molecule inhibitor of STAMBP deubiquitinase activity, BC-1471, decreases NALP7 protein levels and suppresses IL-1beta release after TLR agonism.

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The new findings of this study are that (i) NALP7 is a ubiquitinated protein degraded within the lysosome, (ii) LPS and Pam3CSK4 preserve NALP7 protein by disrupting lysosomal trafficking, (iii) NALP7 abundance is modulated by the DUB, STAMBP and (iv) pharmacologic targeting of STAMBP deubiquitinase activity using a novel chemical entity abrogates induction of NALP7 levels in response to these PAMPs, thereby significantly suppressing IL-1beta secretion.

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As can be seen there was a tendency for animals treated with corticosterone and those treated with a-MSH to have a lower efficiency as compared to animals treated with a placebo.

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First and foremost is the ob- servation that a-MSH stimulates corticosterone pro- duction in glomerulosa cells from normal animals at levels at least three orders of magnitude lower than in fasciculat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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These two sets of data strongly suggest that a-MSH stimulates corticosterone production in glomerulosa 100 [y " 50 Glomerulosa corticosterone 100 r% maximal response 50 / / Glomerulosa aldosterone> ' [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Corticosterone production is stimulated by a-MSH in cells from normal animals at concentrations within the normal range for circulating plasma (~ 3 x lO ^ ^ mol/l), while aldosterone is stimulated by [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Other workers [33] have found that a-MSH at the levels we have used stimulates aldoster- one but not corticosterone in cells from normal rats.

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They nevertheless show comparable changes in steroid profile with sodium restriction, and in tissue from control animals, a-MSH stimulated corticosterone, 18- hydroxycorticosterone and aldosterone (cf[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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STAMBP affects ADCY

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Α-MSH binds to MC1R (melanocortin-1 receptor) on the cell surface and activates adenylate cyclase, which leads to an elevated level of intracellular cAMP ( xref ).

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In addition, it was found that adenylate cyclase activities stimulated by a-MSH, [Nle4] a-MSH, or NaF were enhanced by Mn2+.

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On binding to the MC1-R, α-MSH activates adenylate cyclase which, in turn, causes an increase in intracellular cAMP.

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Α-MSH was reported to bind melanocortin 1 receptor (MC1R) and activate intracellular adenylate cyclase, which in turn catalyzes ATP to cAMP and activates cAMP-dependent PKA.

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Α-MSH binds to melanocortin 1 receptor and activates adenylyl cyclase, increasing the intracellular cyclic adenosine monophosphate (cAMP) level [5,6] .

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Α-MSH acts on its receptor (melanocortin1 receptor) and activates adenylate cyclase, which causes formation of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP).

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In Cloudman S91 mouse melanoma cells, a-MSH activates adenylate cyclase (Bitensky et al., 1972), * Permanent address : Departmento de Fisiologia, Institute de Biociencias, Universidade de Sao Paulo, C[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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STAMBP affects TYR

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STAMBP activates TYR.

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STAMBP activates TYR. 5 / 5

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a-melanocyte-stimulating hormone (a-MSH), secreted by the intermediate lobe of the pituitary, induces eumelanin synthesis in murine melanocytes by binding to melanocortin 1-receptor (MC1-R) and activa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Tyrosinase activity was enhanced 2- to 3-fold above control by the analogue, but only 1- to 2-fold above control by a-MSH at this 24 h time period.

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This finding>, c is in accordance with our previous results [17,18] which ' showed that a-MSH and ACTH did not stimulate ty rosinase activity during the logarithmic growth phase of B 16-G4F cells, ind[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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XREF_BIBR In the recent study by Hur, XREF_BIBR luteolin did not inhibit tyrosinase activation directly, but it concentration-dependently inhibited tyrosinase activation and melanin generation increase by a-MSH in the B16 melanoma cell as well as cAMP generation by MSH and forskolin, which identified the action mechanism of its whitening action generation.

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A-MSH and NDP-MSH induce skin darkening in man (Lerner and McGuire, 1961; Levine et al., 1991) and have recently been shown to stimulate tyrosinase activity, increase melanogenesis and induce dendrici[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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STAMBP increases the amount of TYR.

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STAMBP increases the amount of TYR. 2 / 2

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LHMW also suppressed the α-MSH-induced increased expression of tyrosinase, tyrosinase-related protein 1 (TRP1), and dopachrome tautomerase (DCT) at the protein and mRNA levels.

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Our results showed that 7,3′,4′-THIF inhibited the α-MSH-induced tyrosinase, TYRP-1, TYRP-2 and MITF expression and CREB phosphorylation.

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STAMBP affects Ubiquitin

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STAMBP inhibits Ubiquitin.

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STAMBP inhibits Ubiquitin. 2 / 3

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Immunoblot analysis revealed that ubiquitin chains were completely degraded by AMSH but neither by OTUB1 nor the GST control, further supporting our finding that TRIAD3 synthesises K63 linked ubiquitin chains in vitro, full length TRIAD3 protein as well as the TRIAD3-RBR 845 fragment.

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Mutated STAMBP inhibits Ubiquitin. 1 / 1

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In cells, a dominant negative AMSH mutant caused an accumulation of ubiquitin at endosomes.

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STAMBP activates Ubiquitin.

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STAMBP activates Ubiquitin. 3 / 3

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For the AMSH treatment, substrates were modified with 400 muM wild-type ubiquitin, then treated with 20 muM AMSH for 30 minutes at RT before analysis by SDS-PAGE and visualization by 5-FAM fluorescence on a ChemiDoc (Bio-Rad).

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71 In contrast to PAR2, USP8 (or AMSH) does not impact CXCR4 ubiquitination but instead modulates the ubiquitin status of ESCRT-0 that is ubiquitinated by the E3 ligase AIP4, 23 reinforcing the idea that ubiquitination of the transport machinery represents an important regulatory event in GPCR trafficking.

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STAMBP affects dopamine

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STAMBP activates dopamine. 6 / 6

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The mode of action of a-MSH stimulating the DA system in mediating hypothermia and hypermotility differs from the mode of action of d-amphetamine.

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Versteeg, D.; De Crom, M.; Mulder, A. ACTH (, _ z,) and a-MSH antagonize dopamine receptor mediated inhibition of striatal dopamine and acetylcholine release.

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A-MSH causes an increase in the uptake of tritiated dopamine by crude synaptosomes obtained from rat caudate putamen (CP).

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Versteeg, D.; De Crom, M.; Mulder, A. ACTH (1-24) and a-MSH antagonize dopamine receptor mediated inhibition of striatal dopamine and acetylcholine release.

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VERSTEEG, D. H. G., DECROM, M. P. G. and MULDER, A. H. (1986) ACTH (1-14) and a-MSH antagonize dopamine receptor mediated inhibition of striatal dopamine and acetylcholine release.

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The changes that we observed in [: ~ H] DA uptake and DA content in CP preparations, induced by a-MSH, could reflect that nerve terminals can alter the transport mechanism in response to needs generat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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NPY affects STAMBP

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NPY inhibits STAMBP.

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NPY inhibits STAMBP. 3 / 3

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Comparison of dopamine- and NPY induced inhibition of the aMSH secretion (A) and cAMP release (B) in neurointermediate lobes.

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Therefore, in the present study we have investigated the possibility that NPY inhibits a-MSH secretion from Xenopus melanotropes by binding to a specific receptor that inhibits cAMP production and occ[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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NPY (13-36) did not inhibit a-MSH secretion at any concentration tested.

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NPY activates STAMBP.

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NPY activates STAMBP. 3 / 3

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Reversibility of PYY- and NPY induced inhibition of a-MSH secretion in freshly dissected neurointermediate lobes.

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Hypothalamic integration of immune function and metabolism.increased body weight, decreased cytokines production and increased expression of NPY and decreased a-melanocyte-stimulating hormone (a-MSH) in hypothalamic nuclei.

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One such study carried out by Danger et al. (1985) demonstrated that NPY elicited a-MSH release from the pituitary.

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STAMBP affects MCRs

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STAMBP activates MCRs. 5 / 5

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Instead, we hypothesize that an in vitro interaction between MCRs and GPR139 resulted in transactivation of the phospholipase C pathway through ACTH, α-MSH, and β-MSH activation of MCRs.

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Even though these hormones are derived from different regions of the precursor POMC, because they share a core binding sequence His-Phe-Arg-Trp (HFRW), which is required for binding and activation of the receptors, ACTH can activate all five MCRs, whereas α-MSH can activate all MCRs except MC2R ( xref ).

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The MC2R is specifically activated by ACTH, while the other MCRs can be activated by α-MSH as well as ACTH xref .

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Other ligands like ACTH can also stimulate MC1R while α-MSH can activate other MCRs.

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As the major endogenous agonist in CNS, α-MSH activates neural MCRs to induce a negative energy balance, consisting the catabolic arm of melanocortin system [ xref ].

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BMPR1B affects STAMBP

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BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads.

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STAMBP affects CAMP

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STAMBP increases the amount of CAMP.

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STAMBP increases the amount of CAMP. 2 / 2

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STAMBP activates CXCR4.

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Modified STAMBP activates CXCR4. 1 / 1

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Depletion of AMSH by siRNA does not affect CXCR4 degradation, but expression of AMSH dominant negative constructs enhances HRS or STAM ubiquitination and inhibits CXCR4 degradation.

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TCHH affects STAMBP

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TCHH inhibits STAMBP. 4 / 4

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In addition, THL could inhibit the JAMM protease family AMSH, which cleaves K63-linked ubiquitin chains of endosomal proteins xref , xref .

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AMSH was inhibited by THL with an IC 50 that was ~ 8-fold higher (4 muM) than that measured for Rpn11, and inhibition was reversible by Zn (cyclen) 2+ (XREF_FIG).

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AMSH was inhibited by THL with an IC 50 that was ∼8-fold higher (4 μM) than that measured for Rpn11, and inhibition was reversible by Zn(cyclen) 2+ ( xref ).

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In addition, THL could inhibit the JAMM protease family AMSH, which cleaves K63 linked ubiquitin chains of endosomal proteins XREF_BIBR, XREF_BIBR.

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STAMBP affects STAM

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The gene encoding AMSH (associated molecule with a Src homology 3 domain), a deubiquitinating enzyme, was up-regulated as well as, three genes involved in the ESCRT pathway, ESCRT-0 (STAM (signal transducing adaptor molecule)) and ESCRT-III (CHMP (charged multivesicular body proteins) 2 and 4).

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Further, the DUB activity of STAMBP modulates the ubiquitination of ESCRT proteins STAM and hepatocyte growth factor regulated tyrosine kinase substrate (HRS), but does not affect their degradation or stability XREF_BIBR XREF_BIBR.

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STAMBP affects NFkappaB

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This inhibition of NF-κB activation by α-MSH results in the suppression of the wide range of inflammatory activity of macrophages and neutrophils ( xref - xref , xref ).

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Inhibition of NF-κB activation by α-MSH was also confirmed in human glioma cells (A172) that are of a macrophage phenotype [8] .

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The results indicated that α-MSH alone did not activate NF-κB, but SA-LPS-induced NF-κB activation was inhibited in a dose-dependent manner both in HMC-1 ( Fig. 4A1 ) and BM-[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The results shown in Fig. 1A indicate that α-MSH alone did not activate NF-κB, but SA-LPS-induced NF-κB activation was inhibited in a dose-dependent manner and at 10 4 pM [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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PRCP affects STAMBP

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PRCP inhibits STAMBP. 4 / 4

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PRCP inactivates α-MSH by the removal of the N-terminal valine residue.

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Recently Wallingford and colleagues have identified an enzyme, prolylcarboxypeptidase (PRCP), that inactivates α-MSH by removing the C-terminal valine residue ( xref ).

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The serine protease prolylcarboxypeptidase (PRCP) inactivates α-MSH by catalyzing cleavage at the carboxyl terminal Pro-Val bond, producing inactive α-MSH 1–12 . suggests PRCP could have an appetite stimulating (orexigenic) effect [ xref , xref ].

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Obesity is known to cause inflammation and insulin resistance in the vasculature and non-vascular tissues involved in glucose metabolism. xref Evidence suggests that hyperglycemia may contribute to defective NO-dependent vasodilation in diabetes. xref The inducible NO synthase (iNOS) expression is elevated in adipose tissue of obese people compared to those of lean people xref and is a mediator of inflammation and a key enzyme in insulin resistance. xref The colocalization of α-MSH 1–13 receptors (MC4R) with iNOS has been reported, suggesting a role for α-MSH 1–13 in obese people. xref The inactivation of α-MSH 1–13 by PRCP provides a positive feedback loop for postprandial enhancement of food intake and inflammation by inhibiting α-MSH 1–13 function, as shown in xref . xref Since PRCP regulates the anorectic action of α-MSH 1–13 , this study highlights the presence of a newly recognized interaction between inflammation, obesity, and the expression and activity of PRCP ( xref ). xref In view of the above studies, we consider that PRCP may be a key player in the obesity-associated metabolic complications, inflammatory response, and the host defense mechanism.

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Bromocriptine affects STAMBP

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Bromocriptine inhibits STAMBP.

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Bromocriptine inhibits STAMBP. 3 / 3

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It can be seen that while all doses of bromocryptine decreased plasma a-MSH concentrations the decrease was only significant (p < 0.05) at the lowest dose (3.12 Ag).

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Under the conditions of the present experiments it is quite clear that none of the prostaglandins tested is effective eliciting a-MSH secretion in vitro.

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Since it was previously demonstrated that PGEs potentiate the stimulatory effect of TRH on TSH release in vivo (19) and in vitro (14, 16), it was decided to investigate the possible regulatory roles o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Baclofen affects STAMBP

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Baclofen inhibits STAMBP. 3 / 3

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STAMBP inhibits SMAD6. 3 / 3

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It has been proposed that AMSH sequesters SMAD6, thus impeding its inhibitory role on the BMP pathway and thereby resulting in a prolonged BMP signalling.

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Smad6 can be sequestered by the protein AMSH upon nuclear export in response to BMP (Itoh et al., 2001).

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AMSH has been reported to antagonise Smad6 function, and promote BMP signalling.

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STAMBP affects Melanin

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STAMBP activates Melanin. 3 / 3

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XREF_BIBR In addition, alpha-melanocyte-stimulating hormone (a-MSH), ligand of the melanocortin 1 receptor (MC1R), not only induces melanin synthesis but has also an ability to reduce UVB induced DNA damage by enhanced nucleotide excision repair (NER) in melanocytes, therefore directly influencing UV resistance.

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Melanotropic peptides such as a-melanocyte-stimulating hormone (a-MSH) induce formation and release of melanin pigment in B16-F1 cells.

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STAMBP affects MC5R

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STAMBP activates MC5R. 3 / 3

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ACTH (1–39) or α-MSH can activate MC1R, MC3R, MC4R, and MC5R ( xref ), but MC2R can only be activated by ACTH and not by α-MSH or other analogs ( xref ).

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The present study is aiming to comprehensively investigate the signaling pathways promoted by α-MSH-activated MC5R and address the regulation of the receptor internalization/desensitization mechanisms[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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STAMBP affects MC3R

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STAMBP activates MC3R. 3 / 3

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MC3R and MC4R in these neurons can be activated by α-MSH or inactivated by AgRP to exhibit negative or positive energy balance, respectively [ xref ].

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ACTH (1–39) or α-MSH can activate MC1R, MC3R, MC4R, and MC5R ( xref ), but MC2R can only be activated by ACTH and not by α-MSH or other analogs ( xref ).

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STAMBP affects MAPK

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STAMBP activates MAPK. 3 / 3

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STAMBP promotes lung adenocarcinoma metastasis by regulating the EGFR and MAPK signaling pathway.

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The overexpression of STAMBP triggered the activation of MAPK signaling after epidermal growth factor treatment.

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In contrast, the R163Q variant displayed a selective loss of α-MSH-induced MAPK activation; whereas responsiveness to the small-molecule agonist BMS-470539 was preserved.

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RNF11 affects STAMBP

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RNF11 inhibits STAMBP. 3 / 3

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Therefore, RNF11 rescues TGFbeta signalling and causes the degradation of AMSH through a Smurf2 mediated pathway, the implications of which are discussed further below.The TGFbetas belong to a super f[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Concomitantly, RNF11 cooperates with Smurf2 to degrade AMSH, an ubiquitin isopeptidase (a de-ubiquitination enzyme, DUB) that enhances TGFbeta signalling and EGFR-endosomal recycling [3,63].

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The potential functions of RNF11 mediated degradation of AMSH in breast cancer are discussed.

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MSLN affects STAMBP

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MSLN activates STAMBP. 3 / 3

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However, it is not known whether MPF potentiates the biological response to a-MSH, that is increased melanin production in BI 6 melanoma cells, nor is it known whether ~ F affects adenylate cyclase ac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In addition, another peptide derived from pro- opiocortin, ~-endor- p, ~ n, which does not possess the common heptapeptide sequence, may have both melanogenic and melanotrophic effects - there is evid[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Investigation of the response to peptides derived from the latter portion of pro opiocortin,/$-endorphin and its derivatives, Met enkephalin and MPF, showed that these failed to stimulate adenylate cy[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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17alpha-ethynylestradiol affects STAMBP

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17alpha-ethynylestradiol increases the amount of STAMBP. 3 / 3

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Estrogen as indicated earlier does not increase the baseline levels of a-MSH, but rather alters the pattern of its release.

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Estrogen affects STAMBP

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Estrogen inhibits STAMBP.

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Estrogen inhibits STAMBP. 2 / 2

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STAMBP activates naloxone. 2 / 2

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In contrast a dominant negative form of CHMP3 prevents AMSH localization to the endosome, which in turn inhibits EGFR degradation [XREF_BIBR].

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2,3,7,8-tetrachlorodibenzodioxine affects STAMBP

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2,3,7,8-tetrachlorodibenzodioxine increases the amount of STAMBP. 2 / 2

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Potassium(1+) inhibits STAMBP. 1 / 1

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In the pituitary, high potassium levels inhibited a-MSH release, probably as a consequence of the depolarization inducing DA release [22].

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Potassium(1+) activates STAMBP.

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Potassium(1+) activates STAMBP. 1 / 1

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STAMBP inhibits cell migration. 1 / 1

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This certainly raises the possibility that the processes of proliferation, migration may be inhibited by NF-κB. An inhibition of melanoma cell migration by α-MSH has been also observed in another inflammatory context [ xref ].

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STAMBP activates cell migration.

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STAMBP activates cell migration. 1 / 1

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Mutated STAMBP inhibits MYC. 1 / 1

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An AMSH mutant lacking the JSH region dominant-negatively suppressed c- myc induction, thereby indicating involvement of the JSH region in transcriptional regulation [13].

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STAMBP decreases the amount of MYC.

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Mutated STAMBP decreases the amount of MYC. 1 / 1

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Since both Grb2 and STAM1 have been implicated in neuronal survival signaling [12-14], we speculate that the neuronal cell death in the AMSH deficient brain might be caused by the lack of interaction [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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STAMBP bound to STAM activates Death. 1 / 1

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4,4'-diaminodiphenylmethane affects STAMBP

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4,4'-diaminodiphenylmethane decreases the amount of STAMBP. 1 / 1

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