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J. Biol. Chem., Vol. 279, Issue 33, 34570-34577, August 13, 2004

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Extracellular Signal-regulated Kinase Activated by Epidermal Growth Factor and Cell Adhesion Interacts with and Phosphorylates Vinexin^*

Masaru Mitsushima, Akira Suwa, Teruo Amachi, Kazumitsu Ueda, and Noriyuki Kioka

From the Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

Extracellular signal-regulated kinase 1/2 (ERK1/2) is activated by various extracellular stimuli including growth factors and cytokines and plays a pivotal role in regulating cell proliferation and differentiation by phosphorylating nuclear transcription factors. Recently, it was reported that activated ERK1/2 also concentrates at adhesion sites and regulates cell spreading and migration. Vinexin is a focal adhesion protein regulating both cell spreading and growth factor signaling. We show here that vinexin was directly phosphorylated by ERK1/2 upon stimulation with growth factors. ERK1/2 phosphorylated the linker region of vinexin between the second and third SH3 domains. Site-directed mutagenesis revealed that ERK2 mainly phosphorylated the serine 189 residue of vinexin . Furthermore, vinexin interacted with ERK1/2 both in vitro and in vivo. Vinexin interacted with the active but not inactive form of ERK1/2. A putative DEF (docking for ERK FXFP) domain located in the linker region of vinexin was required for the interaction with ERK1/2 and efficient phosphorylation of vinexin by ERK2. Finally, we showed that cell adhesion to fibronectin also induced the association of vinexin with ERK2 and the phosphorylation of vinexin . Furthermore, vinexin and ERK were co-localized to the periphery of cells during cell spreading on fibronectin. Together, these results suggest that vinexin is a novel substrate of ERK2 and may play roles in ERK-dependent cell regulation during cell spreading as well as in growth factor-induced responses.

Received for publication, March 1, 2004 , and in revised form, May 10, 2004.

Note Added in Proof—The binding surface of ERK for the DEF domain was determined by Lee et al. (48). The surface was reported to be exposed after ERK is activated. This may explain why vinexin binds only to activated ERK.

^* This work was supported in part by The Asahi Glass Foundation and a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology 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. Fax: 81-75-753-6104; E-mail: nkioka{at}kais.kyoto-u.ac.jp.

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