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J. Biol. Chem., Vol. 279, Issue 31, 32308-32315, July 30, 2004

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Phosphorylation and Recruitment of Syk by Immunoreceptor Tyrosine-based Activation Motif-based Phosphorylation of Tamalin^*

Masayuki Hirose, Jun Kitano, Yoshiaki Nakajima, Koki Moriyoshi, Shigeru Yanagi, Hirohei Yamamura, Takanori Muto¶, Hisato Jingami¶, and Shigetada Nakanishi||

From the Department of Biological Sciences, Faculty of Medicine, and the Department of Molecular and System Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, the Department of Genome Sciences, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650-0017, and the ^¶Department of Molecular Biology, Biomolecular Engineering Research Institute, Suita, Osaka 565-0874, Japan

Tamalin is a scaffold protein that forms a multiple protein assembly including metabotropic glutamate receptors (mGluRs) and several postsynaptic and protein-trafficking scaffold proteins in distinct mode of protein-protein association. In the present investigation, we report that tamalin possesses a typical immunoreceptor tyrosine-based activation motif (ITAM), which enables Syk kinase to be recruited and phosphorylated by the Src family kinases. Coimmunoprecipitation analysis of rat brain membrane fractions showed that tamalin is present in a multimolecular protein assembly comprising not only mGluR1 but also c-Src, Fyn, and a protein phosphatase, SHP-2. The protein association of both tamalin and c-Src, as determined by truncation analysis of mGluR1 in COS-7 cells, occurred at the carboxyl-terminal tail of mGluR1. Mutation analysis of tyrosine with phenylalanine in COS-7 cells revealed that paired tyrosines at the ITAM sequence of tamalin are phosphorylated preferentially by c-Src and Fyn, and this phosphorylation can recruit Syk kinase and enables it to be phosphorylated by the Src family kinases. The phosphorylated tyrosines at the ITAM sequence of tamalin were highly susceptible to dephosphorylation by protein-tyrosine phosphatases in COS-7 cells. Importantly, tamalin was endogenously phosphorylated and associated with Syk in retinoic acid-treated P19 embryonal carcinoma cells that undergo neuron-like differentiation. The present investigation demonstrates that tamalin is a novel signaling molecule that possesses a PDZ domain and a PDZ binding motif and mediates Syk signaling in an ITAM-based fashion.

Received for publication, January 18, 2004 , and in revised form, May 12, 2004.

^* This work was supported in part by research grants from the Ministry of Education, Sciences, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Biological Sciences, Faculty of Medicine, Kyoto University, Yoshida-Konoe Cho, Sakyo Ku, Kyoto 606-8501, Japan. Tel.: 81-75-753-4437; Fax: 81-75-753-4404; E-mail: snakanis{at}phy.med.kyoto-u.ac.jp.

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