Journal Article

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

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

in Human Molecular Genetics

Volume 9, issue 1, pages 125-132
Published in print January 2000 | ISSN: 0964-6906
Published online January 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.1.125
Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance

Show Summary Details

Preview

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.

Journal Article.  5422 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.