Human Molecular Genetics, 2000, Vol. 9, No. 1 125-132
© 2000 Oxford University Press
Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance
1Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai 980-8575, Japan, 2National Institute of Deafness and Other Communication Disorders, Bethesda, MD 20892, USA, 3Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA, 4National Institute of Mental Health, Bethesda, MD 20892, USA and 5Research Institute, Saitama Cancer Center, Ina, Saitama 362-0806, Japan
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 GSK3ß 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 GSK3ß and impaired MITF function. These findings suggest that the Ser298 is important for MITF function and is phosphorylated probably by GSK3ß.
+ Present address: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo 060-8638, Japan
§ Present address: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo 113-8602, Japan
¶ Present address: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
To whom correspondence should be addressed at: Research Institute, Saitama Cancer Center, 818 Komuro, Ina, Saitama 362-0806, Japan. Tel: +81 48 722 111 ext. 4693; Fax +81 48 722 1739; Email: mtachiba@cancer-c.pref.saitama.jp
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