PXD010665-2

PXD010665 is an original dataset announced via ProteomeXchange.

Title	BRAF/MAPK and GSK3b signalling signaling converge to control MITF nuclear export
Description	The close integration of the MAPK, PI3K and WNT signaling pathways underpins much of development and is deregulated in cancer. In principle, combinatorial post-translational modification of key lineage–specific transcription factors would be an effective means to integrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia associated transcription factor, MITF, plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts and mast cells, and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell cycle progression, cell migration, metabolism and lysosome biogenesis. Yet how the activity of this key transcription factor is controlled remains poorly understood. Here we show that GSK3b, downstream from both the PI3K and Wnt pathways, and BRAF/MAPK signaling converge to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3b, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activating a previously unrecognized hydrophobic export signal. Nonmelanocyte MITF isoforms exhibit poor regulation by MAPK signaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import-export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:33:54.133.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD010665
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Georgina Berridge
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	HNE; GG; PropylNAGthiazoline; Phytochromobilin; Bacillosamine; Hex; Phosphopantetheine; Methylphosphonate; Bromobimane; Decanoyl; CAMthiopropanoyl; CarbamidomethylDTT; Propionamide; GlycerylPE; BADGE; Deamidated; Methylamine; DHP; CHDH; Myristoyl; NO_SMX_SEMD; Argbiotinhydrazide; Octanoyl; Glycosyl; Gln->pyro-Glu; Met->Hsl; Diethylphosphate; Guanidinyl; Menadione-HQ; DAET; DeStreak; BHTOH; NA-LNO2; Chlorination; Ammonia-loss; Nethylmaleimide+water; Ethylphosphate; Cys->CamSec; ISD_z+2_ion; Oxidation; Diphthamide; Piperidine; AEC-MAEC; HMVK; Ethanedithiol; Carboxy; O-pinacolylmethylphosphonate; BITC; Phycoerythrobilin; 4-ONE; PET; Cation:Na; LG-lactam-R; Nitrosyl; Palmitoleyl; PyMIC; Sulfo; MG-H1; Malonyl; Glutathione; Formyl; Carbamyl; LG-anhydrolactam; Delta:H(2)C(3)O(1); Sulfide; Met->Aha; Tyr->Dha; Ammonium; 2-succinyl; Menadione; NA-OA-NO2; Crotonaldehyde; Met->Hse; Cytopiloyne; Amidated; Diethyl; Nethylmaleimide; Cys->Dha; Thiazolidine; Lys->AminoadipicAcid; Ethanolyl; EGCG2; Phospho; Cys->ethylaminoAla; Hep; PEITC; Propargylamine; Acetyl; Methylthio; Carboxymethyl; 4-ONE+Delta:H(-2)O(-1); Cation:Ag; HexNAc; Carbamidomethyl; Cation:Ca[II]; Cysteinyl; 3sulfo; Biotin-PEO-Amine; HNE+Delta:H(2); cGMP+RMP-loss; Trioxidation; trifluoro; CarboxymethylDTT; GluGluGluGlu; Arg->Npo; dHex; Delta:H(2)C(2); GeranylGeranyl; Ethyl; Cation:Li; BHT; Isopropylphospho; LG-pyrrole; AEBS; Pyridylacetyl; LG-Hlactam-R; Phosphopropargyl; Pyridylethyl; HNE-Delta:H(2)O; TNBS; Didehydro; Cytopiloyne+water; Trp->Kynurenin; Glu; SMA; HexN; Diisopropylphosphate; Lys->Allysine; Heme; LG-anhyropyrrole; ethylamino; maleimide; Dehydrated; Biotin; Dioxidation; Ethyl+Deamidated; Benzoyl; glycidamide
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-08-02 05:36:42	ID requested
1	2024-10-08 12:51:31	announced
⏵ 2	2024-10-22 05:33:54	announced	2024-10-22: Updated project metadata.

Ngeow KC, Friedrichsen HJ, Li L, Zeng Z, Andrews S, Volpon L, Brunsdon H, Berridge G, Picaud S, Fischer R, Lisle R, Knapp S, Filippakopoulos P, Knowles H, Steingr, í, msson E, Borden KLB, Patton EE, Goding CR, BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export. Proc Natl Acad Sci U S A, 115(37):E8668-E8677(2018) [pubmed]

10.6019/PXD010665;

10.1073/pnas.1810498115;

curator keyword: Biological

submitter keyword: MITF | melanoma | MAPK | nuclear export | GSK3b

Roman Fischer
contact affiliation	Target discovery Institute
contact email	roman.fischer@ndm.ox.ac.uk
lab head
Georgina Berridge
contact affiliation	University of Oxford
contact email	georgina.berridge@ndm.ox.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD010665

PRIDE project URI

• PRIDE
  1. PXD010665
     1. Label: PRIDE project
     2. Name: BRAF/MAPK and GSK3b signalling signaling converge to control MITF nuclear export