Pathway Human Homo sapiens

Transcriptional and post-translational regulation of MITF-M expression and activity

R-HSA-9856649 in Reactome release 97: under MITF-M-regulated melanocyte development, with 62 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9856649 (mouse), R-RNO-9856649 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9856649.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2024-03-27
Events inside: 37, counted from the record

Melanocytes, neurons and glia all arise from precursor cells derived from neural crest cells. Cells that will give rise to neurons and glia migrate away from the neural crest earlier and in a ventral pattern, while cells that will give rise to melanocytes leave the neural crest later and migrate dorsolaterally. Nevertheless, melanocytes can also arise in an alternate pathway from dual Schwann cell/melanocyte precursors or by dedifferentiation from Schwann cells, a derivative of the glial lineage (reviewed in Mort et al, 2015). MITF-M is a key regulator of melanocyte development, and its expression distinguishes the melanocyte fate from that of glial and neural cells. MITF-M expression is repressed in precursors through the activity of FOXD3 and SOX2. Depending on the species, these transcription factors may either bind directly to elements in the MITF-M promoter to repress transcription, or may act independently of DNA binding by disrupting protein-protein interactions that promote transcriptional activity (Nitzan et al, 2013a,b; Curran et al, 2009, 2010; Adameyko et al, 2012; reviewed in Mort et al, 2015; White and Zon, 2008; Goding and Arnheiter, 2019). FOXD3 and SOX2 expression, in turn, are regulated by a cascade of other transcription factors, including ZIC1, PAX3, SNAIL2 and SOX9 (reviewed in Mort et al, 2015; Goding and Arnheiter, 2019).

Relief of FOXD3 mediated repression may depend in part on HDAC1, as well as on down regulation of SNAIL2 (Ignatius et al, 2008; Greenhill et al, 2011; Nitzan et al, 2013a, b). MITF-M expression in unpigmented but committed melanoblasts depends on PAX3 and SOX10 binding at the promoter as well as on WNT, EDNRB and KIT signaling (reviewed in Mort et al, 2015; White and Zon, 2008; Goding and Arnheiter, 2019). Initial expression of MITF-M also contributes to downregulation of FOXD3 and SOX2 establishing a positive feedback loop that reinforces commitment to the melanocyte fate (reviewed in Mort et al, 2015; Goding and Arnheiter, 2019).

In addition to transcriptional regulation, MITF-M activity is also controlled by post translational modifications, although the significance of these modifications is not always clear. SUMOylation, ubiquitination and phosphorylation downstream of MAPK, WNT and AKT signaling can all impact the stability, localization or activity of MITF-M (reviewed in Goding and Arnheiter, 2019), and acetylation regulates the occupancy of target promoters, decreasing occupancy at differentiation-specific promoters (Louphrasitthiphol et al, 2020, 2023).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 62 genes in this human pathway; showing 1 to 62, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAIMP1	AuthorityHGNC:10648	Mapping file id9255 NCBI file	EvidenceTAS
GeneAIMP2	AuthorityHGNC:20609	Mapping file id7965 NCBI file	EvidenceTAS
GeneAKT3	AuthorityHGNC:393	Mapping file id10000 NCBI file	EvidenceTAS
GeneALX3	AuthorityHGNC:449	Mapping file id257 NCBI file	EvidenceIEA, TAS
GeneCDH1	AuthorityHGNC:1748	Mapping file id999 NCBI file	EvidenceTAS
GeneCREB1	AuthorityHGNC:2345	Mapping file id1385 NCBI file	EvidenceTAS
GeneCREBBP	AuthorityHGNC:2348	Mapping file id1387 NCBI file	EvidenceIEA, TAS
GeneCSF1	AuthorityHGNC:2432	Mapping file id1435 NCBI file	EvidenceTAS
GeneCTNNB1	AuthorityHGNC:2514	Mapping file id1499 NCBI file	EvidenceTAS
GeneDARS1	AuthorityHGNC:2678	Mapping file id1615 NCBI file	EvidenceTAS
GeneEDN1	AuthorityHGNC:3176	Mapping file id1906 NCBI file	EvidenceTAS
GeneEDN3	AuthorityHGNC:3178	Mapping file id1908 NCBI file	EvidenceTAS
GeneEDNRB	AuthorityHGNC:3180	Mapping file id1910 NCBI file	EvidenceTAS
GeneEEF1E1	AuthorityHGNC:3212	Mapping file id9521 NCBI file	EvidenceTAS
GeneEP300	AuthorityHGNC:3373	Mapping file id2033 NCBI file	EvidenceIEA, TAS
GeneEPRS1	AuthorityHGNC:3418	Mapping file id2058 NCBI file	EvidenceTAS
GeneFOXD3	AuthorityHGNC:3804	Mapping file id27022 NCBI file	EvidenceIEA, TAS
GeneGSK3B	AuthorityHGNC:4617	Mapping file id2932 NCBI file	EvidenceTAS
GeneHDAC1	AuthorityHGNC:4852	Mapping file id3065 NCBI file	EvidenceTAS
GeneHINT1	AuthorityHGNC:4912	Mapping file id3094 NCBI file	EvidenceTAS
GeneIARS1	AuthorityHGNC:5330	Mapping file id3376 NCBI file	EvidenceTAS
GeneID1	AuthorityHGNC:5360	Mapping file id3397 NCBI file	EvidenceTAS
GeneKARS1	AuthorityHGNC:6215	Mapping file id3735 NCBI file	EvidenceTAS
GeneKIT	AuthorityHGNC:6342	Mapping file id3815 NCBI file	EvidenceTAS
GeneKITLG	AuthorityHGNC:6343	Mapping file id4254 NCBI file	EvidenceTAS
GeneLARS1	AuthorityHGNC:6512	Mapping file id51520 NCBI file	EvidenceTAS
GeneLEF1	AuthorityHGNC:6551	Mapping file id51176 NCBI file	EvidenceTAS
GeneMAPK1	AuthorityHGNC:6871	Mapping file id5594 NCBI file	EvidenceTAS
GeneMAPK3	AuthorityHGNC:6877	Mapping file id5595 NCBI file	EvidenceTAS
GeneMARK3	AuthorityHGNC:6897	Mapping file id4140 NCBI file	EvidenceTAS
GeneMARS1	AuthorityHGNC:6898	Mapping file id4141 NCBI file	EvidenceTAS
GeneMC1R	AuthorityHGNC:6929	Mapping file id4157 NCBI file	EvidenceTAS
GeneMC3R	AuthorityHGNC:6931	Mapping file id4159 NCBI file	EvidenceTAS
GeneMC4R	AuthorityHGNC:6932	Mapping file id4160 NCBI file	EvidenceTAS
GeneMC5R	AuthorityHGNC:6933	Mapping file id4161 NCBI file	EvidenceTAS
GeneMITF	AuthorityHGNC:7105	Mapping file id4286 NCBI file	EvidenceIEA, TAS
GenePAX3	AuthorityHGNC:8617	Mapping file id5077 NCBI file	EvidenceIEA, TAS
GenePOMC	AuthorityHGNC:9201	Mapping file id5443 NCBI file	EvidenceTAS
GenePOU3F2	AuthorityHGNC:9215	Mapping file id5454 NCBI file	EvidenceTAS
GeneQARS1	AuthorityHGNC:9751	Mapping file id5859 NCBI file	EvidenceTAS
GeneRARS1	AuthorityHGNC:9870	Mapping file id5917 NCBI file	EvidenceTAS
GeneRPS6KA1	AuthorityHGNC:10430	Mapping file id6195 NCBI file	EvidenceTAS
GeneSIRT1	AuthorityHGNC:14929	Mapping file id23411 NCBI file	EvidenceTAS
GeneSNAI2	AuthorityHGNC:11094	Mapping file id6591 NCBI file	EvidenceTAS
GeneSOX10	AuthorityHGNC:11190	Mapping file id6663 NCBI file	EvidenceTAS
GeneSOX2	AuthorityHGNC:11195	Mapping file id6657 NCBI file	EvidenceTAS
GeneSOX9	AuthorityHGNC:11204	Mapping file id6662 NCBI file	EvidenceTAS
GeneSUMO1	AuthorityHGNC:12502	Mapping file id7341 NCBI file	EvidenceTAS
GeneTBX3	AuthorityHGNC:11602	Mapping file id6926 NCBI file	EvidenceTAS
GeneTFE3	AuthorityHGNC:11752	Mapping file id7030 NCBI file	EvidenceIEA
GeneTFEB	AuthorityHGNC:11753	Mapping file id7942 NCBI file	EvidenceIEA
GeneTFEC	AuthorityHGNC:11754	Mapping file id22797 NCBI file	EvidenceIEA
GeneTNFSF11	AuthorityHGNC:11926	Mapping file id8600 NCBI file	EvidenceTAS
GeneUBE2I	AuthorityHGNC:12485	Mapping file id7329 NCBI file	EvidenceTAS
GeneWNT3A	AuthorityHGNC:15983	Mapping file id89780 NCBI file	EvidenceTAS
GeneXPO1	AuthorityHGNC:12825	Mapping file id7514 NCBI file	EvidenceTAS
GeneYWHAB	AuthorityHGNC:12849	Mapping file id7529 NCBI file	EvidenceIEA
GeneYWHAE	AuthorityHGNC:12851	Mapping file id7531 NCBI file	EvidenceIEA
GeneYWHAG	AuthorityHGNC:12852	Mapping file id7532 NCBI file	EvidenceIEA
GeneYWHAH	AuthorityHGNC:12853	Mapping file id7533 NCBI file	EvidenceIEA
GeneYWHAZ	AuthorityHGNC:12855	Mapping file id7534 NCBI file	EvidenceIEA
GeneZIC1	AuthorityHGNC:12872	Mapping file id7545 NCBI file	EvidenceTAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

MITF-M-regulated melanocyte developmentR-HSA-9730414160 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.