MITF: A Stream Flowing for Pigment Cells

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.