Reactome | MAPK1-dependent phosphorylation of MITF-M

MAPK1-dependent phosphorylation of MITF-M

Stable Identifier

R-HSA-9824977

Type

Reaction [transition]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

MAPK1-dependent phosphorylation of MITF-M

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

MITF-M is phosphorylated by MAPK1 (also known as ERK2) in response to signaling through KITLG-KIT (Wu et al, 2000). S73 phosphorylation has been suggested to increase the transcription factor activity of MITF-M and promote its interaction with EP300/CBP (Price et al, 1998, Xu et al, 2000). In contrast, other studies have not reported increased interaction with EP300 upon S73 phosphorylation (Sato et al, 1997). S73 phosphorylation primes MITF-M for subsequent phosphorylation by GSK3B at S69, targeting it for nuclear export (Ngeow et al, 2018, reviewed in Goding and Arnheiter, 2019). This has led to a model where signaling through SCF-KIT leads to an S73-dependent increase in MITF-M signaling followed by subsequent downregulation by virtue of nuclear export and/or degradation (reviewed in Goding and Arnheiter, 2019).
KITLG-KIT signaling is implicated in melanocyte differentiation and survival during development. Mutations in the W locus in mouse, where KIT is located, are characterized by macrocytic anemia, lack of hair pigmentation and sterility, and mutations in this region or in the KIT ligand affect proliferation and migration of cell during early embryogenesis (Chabot et al, 1988; Copeland et al, 1990; Geissler et al, 1998). KIT is expressed in melanoblast precursors and contributes to their survival and migration. Consistent with this, KIT mutants do not develop the normal number of melanocytes (Wehrle-Haller and Weston, 1995; Wehrle-Haller et al, 2001; Tabone-Eglinger et al, 2012; Kunisada et al, 1998; reviewed in White and Zon, 2008).
Expression of KIT and MITF appear to be interconnected during embryogenesis in a manner that is not totally elucidated. Although the initial expression of MITF does not appear to depend on activated KIT signaling, KIT signaling does increase the transcriptional activity of MITF, and contributes to the expression of some MITF-M target genes (Hou et al, 2000; Price et al, 1998, Wu et al, 2000, Hemesath et al, 1998). Similarly, MITF expression has been shown to upregulate KIT expression in some systems (Tsujimura et al, 1996; Opdecamp et al, 1997; reviewed in Hou and Pavan, 2008).

Literature References

PubMed ID	Title	Journal	Year
9440696	MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes Hemesath, TJ, Fisher, DE, Takemoto, C, Badalian, T, Price, ER	Nature	1998
22637532	Membrane-bound Kit ligand regulates melanocyte adhesion and survival, providing physical interaction with an intraepithelial niche Wehrle-Haller, B, Jacquier, MC, Wehrle-Haller, M, Tabone-Eglinger, S, Aebischer, N	FASEB J	2012
10694430	Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9 Campisi, J, Haddad, MM, Bischof, O, Yeh, ET, Gong, L, Xu, W, Medrano, EE	Exp Cell Res	2000
30150413	BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export Knapp, S, Patton, EE, Friedrichsen, HJ, Berridge, G, Filippakopoulos, P, Andrews, S, Fischer, R, Goding, CR, Picaud, S, Brunsdon, H, Ngeow, KC, Borden, KLB, Zeng, Z, Steingrímsson, E, Lisle, R, Knowles, H, Volpon, L, Li, L	Proc Natl Acad Sci U S A	2018
10673502	c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi Hemesath, TJ, Fisher, DE, Wells, AG, Fisher, DZ, Wu, M, Takemoto, CM, Horstmann, MA, Price, ER	Genes Dev	2000
9223672	CBP/p300 as a co-factor for the Microphthalmia transcription factor Kouzarides, T, Roberts, K, Cook, A, Gambino, G, Goding, CR, Sato, S	Oncogene	1997
9199364	Melanocyte development in vivo and in neural crest cell cultures: crucial dependence on the Mitf basic-helix-loop-helix-zipper transcription factor Opdecamp, K, Pavan, WJ, Hodgkinson, CA, Arnheiter, H, Nguyen, MT, Nakayama, A	Development	1997
2458842	The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene Geissler, EN, Housman, DE, Ryan, MA	Cell	1988
7536655	Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway Weston, JA, Wehrle-Haller, B	Development	1995
11076759	Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF Arnheiter, H, Panthier, JJ, Hou, L	Development	2000
19002157	Transcriptional and signaling regulation in neural crest stem cell-derived melanocyte development: do all roads lead to Mitf? Pavan, WJ, Hou, L	Cell Res	2008
18786412	Melanocytes in development, regeneration, and cancer White, RM, Zon, LI	Cell Stem Cell	2008
2457811	The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus Stephenson, DA, Chabot, B, Chapman, VM, Bernstein, A, Besmer, P	Nature	1988
9660747	Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia Hemesath, TJ, Bhattacharya, S, Fisher, DE, Takemoto, C, Ding, HF, Yao, TP, Badalian, T, Price, ER	J Biol Chem	1998
31123060	MITF-the first 25 years Arnheiter, H, Goding, CR	Genes Dev	2019
1698554	Mast cell growth factor maps near the steel locus on mouse chromosome 10 and is deleted in a number of steel alleles Copeland, NG, Gilbert, DJ, Donovan, PJ, Jenkins, NA, Anderson, D, Cho, BC, Williams, DE, Lyman, SD, Cosman, D	Cell	1990
11401406	Analysis of melanocyte precursors in Nf1 mutants reveals that MGF/KIT signaling promotes directed cell migration independent of its function in cell survival Weston, JA, Wehrle-Haller, B, Meller, M	Dev Biol	2001
9655813	Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors Miyamoto, A, Hayashi, S, Nishimura, E, Nishikawa, S, Hemmi, H, Yamazaki, H, Kunisada, T, Shultz, LD, Yoshida, H	Development	1998
8695840	Involvement of transcription factor encoded by the mi locus in the expression of c-kit receptor tyrosine kinase in cultured mast cells of mice Nozaki, M, Morii, E, Hashimoto, K, Kondo, T, Takebayashi, K, Moriyama, Y, Kanakura, Y, Tsujimura, T, Kitamura, Y	Blood	1996