Reactome | RPS6KA1-dependent phosphorylation of MITF-M

RPS6KA1-dependent phosphorylation of MITF-M

Stable Identifier

R-HSA-9824994

Type

Reaction [transition]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

RPS6KA1-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 RPS6KA1 (also known as RSK1) at serine S409 downstream of activated SCF-KIT signaling during development (Wu et al, 2000). S409 phosphorylation primes MITF-M for subsequent phosphorylation by GSK3B at serine residues S397, S401 and S405 in the C-terminus, modifications that are associated with degradation of the protein (Ploper et al, 2015, reviewed in Goding and Arnheiter, 2019). Phosphorylation at this site may also affect transcription factor activity of the protein: phosphorylation of MITF-A(-) at S510 (equivalent to S409 of MITF-M (+)) enhances its binding to TP53, leading to increased expression of CDKN1A, while unphosphorylated MITF-A (-) protein elevates TYR gene expression (Wang et al, 2016).
The relationship between MITF and KITLG-KIT during melanocyte differentiation is not totally clear. Mutations of KIT or its ligand are associated with pigmentation defects and depleted levels of mature melanocytes. KIT signaling appears to contribute to the migration and survival of melanoblasts during development (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). MITF-M and KIT also appear to reciprocally affect each other's expression: although KIT does not appear to be required for the initial expression of MITF during development, activated KIT signaling increases the transcription factor activity of MITF to a variable extent at different MITF-M target genes (Hou et al, 2000; Price et al, 1998, Wu et al, 2000, Hemesath et al, 1998). Similarly, expression of MITF-M has been shown to increase expression of KIT in some systems (Tsujimura et al, 1996; Opdecamp et al, 1997; reviewed in Hou and Pavan, 2008)

Literature References

PubMed ID	Title	Journal	Year
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
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
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
27702651	Phosphorylation of MITF by AKT affects its downstream targets and causes TP53-dependent cell senescence Fan, X, Chen, H, Su, Q, Chan, CB, Wang, H, Wang, Y, Zhao, L, Gao, S, Liu, Z, Wang, C	Int J Biochem Cell Biol	2016
31123060	MITF-the first 25 years Arnheiter, H, Goding, CR	Genes Dev	2019
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
18786412	Melanocytes in development, regeneration, and cancer White, RM, Zon, LI	Cell Stem Cell	2008
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
25605940	MITF drives endolysosomal biogenesis and potentiates Wnt signaling in melanoma cells Graeber, TG, Perez, BS, von Euw, E, Ploper, D, Ribas, A, Taelman, VF, Titz, B, Robert, L, De Robertis, EM, Chen, HW	Proc Natl Acad Sci U S A	2015
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
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
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
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
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
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