MITF: A Stream Flowing for Pigment Cells

Authors


Address reprint requests to Masayoshi Tachibana, M.D., Ph.D., 818 Komuro, Ina, Saitama 362-0806 Japan.
E-mail: mtachiba@cancer-c.pref.saitama.jp

Abstract

Microphthalmia-associated t ranscription f actor (MITF) is a transcription factor with a basic-helix-loop-helix-leucine zipper (bHLHZip) structure. Mutations of the MITF gene cause a variety of phenotypes, most notably in pigmented cells, in several species. In humans, haploinsufficiency of MITF causes Waardenburg syndrome type 2, while a dominant-negative mutation causes Tietz syndrome. Four isoforms have been cloned so far: MITF-M is the most abundant and is expressed in neural-crest-derived melanocytes; MITF-A is expressed in various cultured cells including retinal pigment epithelium (RPE) and enriched in RPE of embryonal and developing eyes; MITF-H are expressed in many types of cultured cells and in the heart tissue; MITF-C is expressed in many types of cultured cells, but not in melanocytes. Many growth factor signaling pathways have been implicated for regulation of MITF at both protein and promoter levels. Most notably, Steel factor/c-Kit signaling pathway was linked to phosphorylation of MITF at Ser73 and Ser409 through activation of MAP kinase and RSK-1, respectively. Phosphorylation of MITF is also conducted at Ser298 through GSK3β, although the signaling pathway for this event still remains to be elucidated. IGF-1 and HGF/SF pathways may merge with the c-Kit signaling pathway. WNT and MSH signaling pathways regulate MITF positively at the promoter level. Endothelins may regulate MITF at the protein and promoter levels. MITF is involved in the differentiation, growth and survival of pigment cells, employing a number of signaling pathways.

Abbreviations
αMSH

α-melanocyte-stimulating hormone

ASP

agouti signal protein

bHLHZip

basic-helix-loop-helix-leucine zipper

bFGF

basic fibroblast growth factor

cAMP

cyclic 3′5′-adenosine-monophosphate

DCT

DOPAchrome tautomerase (tyrosinase related-protein 2)

EDN

endothelin

EDNRA

endothelin-A receptor

EDNRB

endothelin-B receptor

HGF

hepatocyte growth factor

ENU

N-ethyl-N-nitrosourea

IGF-I

insulin-like growth factor-I

GSK3

glycogen synthase kinase 3

Msg

mast cell growth factor

MAP

microtubule-associated protein

MAPK

MAP kinase

MSH

melanocyte stimulating hormone

Mitf

microphthalmia-associated transcription factor

Mmcp-6

mouse mast cell protease 6

p70S6K

ribosomal 70 kDa S 6 protein kinase

PBDu

phorbol dibutyrate

Mmp115

melanosomal matrix protein 115

Pebp2

Polyoma virus enhancer binding protein 2

PKA

protein kinase A

MC

protein kinase C

RIPE

retinal pigment epithelium

Rsk

∼90 kDa cell cycle-regulated protein kinase

SF

scatter factor

SI

steel factor

TPA

12-O-tetradecanoylphorbol 13-acetate

TYRP1

tyrosinase-related protein 1

WS1 and WS2

Waardenburg syndrome type 1 and type 2

Ancillary