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J. Biol. Chem., Vol. 279, Issue 33, 34336-34342, August 13, 2004

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The Adaptor Protein Nck1 Mediates Endothelin A Receptor-regulated Cell Migration through the Cdc42-dependent c-Jun N-terminal Kinase Pathway^*

Yuki Miyamoto, Junji Yamauchi, Norikazu Mizuno, and Hiroshi Itoh¶

From the Department of Cell Biology, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan and the Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305-5125

Cell migration plays key roles in physiological and pathological phenomena, such as development and oncogenesis. The adaptor proteins Grb2, CrkII, and Nck1 are composed of only a single Src homology 2 domain and some Src homology 3 domains, giving specificity to each signal transduction pathway. However, little is known about the relationships between their adaptor proteins and cell migration, which are regulated by the G protein-coupled receptor. Here we showed that Nck1, but not Grb2 or CrkII, mediated the inhibition of cell migration induced by the endothelin-1 and endothelin A receptor. The small interference RNA and dominant negative mutants of Nck1 diminished the endothelin-1-induced inhibition of cell migration. Although overexpression of wild-type Nck1 was detected in the cytosol and did not affect cell migration, expression of the myristoylation signal sequence-conjugated Nck1 was detected in the membrane and induced activation of Cdc42 and c-Jun N-terminal kinase, inhibiting cell migration. Taken together, these results suggest that the endothelin A receptor transduces the signal of inhibition of cell migration through Cdc42-dependent c-Jun N-terminal kinase activation by using Nck1.

Received for publication, March 11, 2004 , and in revised form, June 2, 2004.

^* This work was partially supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan (15370057) and by grants from the Yamanouchi Foundation, the Cell Science Research Foundation, and the Ono Medical Research Foundation. 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. Tel.: 81-743-72-5440; Fax: 81-743-72-5449; E-mail: hitoh{at}bs.naist.jp.

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