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J. Biol. Chem., Vol. 280, Issue 45, 37772-37781, November 11, 2005

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JSAP1/JIP3 Cooperates with Focal Adhesion Kinase to Regulate c-Jun N-terminal Kinase and Cell Migration^*

Takahisa Takino1, Mitsutoshi Nakada, Hisashi Miyamori, Yumi Watanabe, Tokiharu Sato¶, Davaakhuu Gantulga¶, Katsuji Yoshioka¶, Kenneth M. Yamada||, and Hiroshi Sato

From the Departments of Molecular Virology and Oncology and ^¶Cell Cycle Regulation, Cancer Research Institute, and Neurosurgery, Division of Neuroscience, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-0934, Japan, ^||Craniofacial Developmental Biology and Regeneration Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4370

c-Jun N-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) (also termed JNK-interacting protein 3; JIP3) is a member of a family of scaffold factors for the mitogen-activated protein kinase (MAPK) cascades, and it also forms a complex with focal adhesion kinase (FAK). Here we demonstrate that JSAP1 serves as a cooperative scaffold for activation of JNK and regulation of cell migration in response to fibronectin (FN) stimulation. JSAP1 mediated an association between FAK and JNK, which was induced by either co-expression of Src or attachment of cells to FN. Complex formation of FAK with JSAP1 and p130 Crk-associated substrate (p130^Cas) resulted in augmentation of FAK activity and phosphorylation of both JSAP1 and p130^Cas, which required p130^Cas hyperphosphorylation and was abolished by inhibition of Src. JNK activation by FN was enhanced by JSAP1, which was suppressed by disrupting the FAK/p130^Cas pathway by expression of a dominant-negative form of p130^Cas or by inhibiting Src. We also documented the co-localization of JSAP1 with JNK and phosphorylated FAK at the leading edge and stimulation of cell migration by JSAP1 expression, which depended on its JNK binding domain and was suppressed by inhibition of JNK. The level of JSAP1 mRNA correlated with advanced malignancy in brain tumors, unlike other JIPs. We propose that the JSAP1·FAK complex functions cooperatively as a scaffold for the JNK signaling pathway and regulator of cell migration on FN, and we suggest that JSAP1 is also associated with malignancy in brain tumors.

Received for publication, May 12, 2005 , and in revised form, August 1, 2005.

^* This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by the Uehara Memorial Foundation (to T. T.). 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.

¹ To whom correspondence should be addressed. Tel.: 81-76-265-2750; Fax: 81-76-234-4505; E-mail: ttakino{at}kenroku.kanazawa-u.ac.jp.

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