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J. Biol. Chem., Vol. 281, Issue 13, 8765-8772, March 31, 2006

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Contact Inhibition of Hepatocyte Growth Regulated by Functional Association of the c-Met/Hepatocyte Growth Factor Receptor and LAR Protein-tyrosine Phosphatase^*

From the Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

Contact inhibition, the inhibition of cell proliferation by tight cell-cell contact is a fundamental characteristic of normal cells. Using primary cultured hepatocytes, we investigated the mechanisms of contact inhibition that decrease the mitogenic activity of hepatocyte growth factor (HGF), focusing on the regulation of c-Met/HGF-receptor activation. In hepatocytes cultured at a sparse cell density, HGF stimulation induced prolonged c-Met tyrosine phosphorylation for over 5 h and a marked mitogenic response. In contrast, HGF stimulation induced transient c-Met tyrosine phosphorylation in <3 h and failed to induce mitogenic response in hepatocytes cultured at a confluent cell density. Treatment of the confluent cells with HGF plus orthovanadate, a broad spectrum protein-tyrosine phosphatase inhibitor, however, prolonged c-Met tyrosine phosphorylation for over 5 h and permitted the subsequent mitogenic response. The mitogenic response to HGF was associated with the duration of c-Met tyrosine phosphorylation even in the sparse cells. We found that the activity and expression of the protein-tyrosine phosphatase LAR increased following HGF stimulation specifically in confluent hepatocytes and not in sparse hepatocytes. LAR and c-Met were associated, and purified LAR dephosphorylated tyrosine-phosphorylated c-Met in in vitro phosphatase reactions. Furthermore, antisense oligonucleotides specific for LAR mRNA suppressed the expression of LAR, allowed prolonged c-Met tyrosine phosphorylation, and led to acquisition of a mitogenic response in hepatocytes even under the confluent condition. Thus functional association of LAR and c-Met underlies the inhibition of c-Met-mediated mitogenic signaling through the dephosphorylation of c-Met, which specifically occurs under the confluent condition.

Received for publication, November 16, 2005 , and in revised form, January 13, 2006.

^* This work was supported by Grant 15590272 from the Ministry of Education, Science, Technology, Sports, and Culture of Japan (to M. M.), Grants 12215082 and 14207005 (to T. N.), and the 21st Century Center of Excellence program (to T. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Div. of Molecular Regenerative Medicine, Dept. of Biochemistry and Molecular Biology, Osaka University Graduate School of Medicine, 2-2-B7 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3783; Fax: 81-6-6879-3789; E-mail: Nakamura{at}onbich.med.osaka-u.ac.jp.

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