Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance

Kazuhisa Takeda, Clifford M Takemoto, Ichiro Kobayashi, Atsushi Watanabe, Yoshitaka Nobukuni, David E. Fisher, Masayoshi Tachibana

Research output: Contribution to journalArticle

Abstract

MITF (microphthalmia-associated transcription factor) is a basic-helix-loop-helix-leucine zipper (bHLHZip) factor which regulates expression of tyrosinase and other melanocytic genes via a CATGTG promoter sequence, and is involved in melanocyte differentiation. Mutations of MITF in mice or humans with Waardenburg syndrome type 2 (WS2)often severely disrupt the bHLHZip domain, suggesting the importance of this structure. Here, we show that Ser298, which locates downstream of the bHLHZip and was previously found to be mutated in individuals with WS2, plays an important role in MITF function. Glycogen synthase kinase 3 (GSK3) was found to phosphorylate Ser298 in vitro, thereby enhancing the binding of MITF to the tyrosinase promoter. The same serine was found to be phosphorylated in vivo, and expression of dominant-negative GSK3β selectively suppressed the ability of MITF to transactivate the tyrosinase promoter. Moreover, mutation of Ser298, as found in a WS2 family, disabled phosphorylation of MITF by GSK3β and impaired MITF function. These findings suggest that the Ser298 is important for MITF function and is phosphorylated probably by GSK3β.

Original languageEnglish (US)
Pages (from-to)125-132
Number of pages8
JournalHuman Molecular Genetics
Volume9
Issue number1
StatePublished - 2000
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Takeda, K., Takemoto, C. M., Kobayashi, I., Watanabe, A., Nobukuni, Y., Fisher, D. E., & Tachibana, M. (2000). Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance. Human Molecular Genetics, 9(1), 125-132.