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J. Biol. Chem., Vol. 283, Issue 1, 496-505, January 4, 2008

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Involvement of Nectin in Inactivation of Integrin _vβ₃ after the Establishment of Cell-Cell Adhesion^*

Yasuhisa Sakamoto, Hisakazu Ogita, Hitomi Komura, and Yoshimi Takai¹

From the Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, Osaka 565-0871, Japan and the Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan

Integrin plays an essential role in the formation of cell-matrix junctions and is also involved in the fundamental cellular functions. In the process of the formation of cell-cell junctions, an immunoglobulin-like cell-cell adhesion molecule nectin initially trans-interacts together and promotes the formation of adherens junctions (AJs) cooperatively with another cell-cell adhesion molecule cadherin. The activation of integrin _vβ₃ is critically necessary for this nectin-induced formation of AJs. However, after the establishment of AJs, integrin _vβ₃ becomes inactive and retains the association with nectin at AJs. The molecular mechanism of this dynamic regulation of integrin _vβ₃ during the formation of AJs remains unclear. We found here that the expression of phosphatidylinositol-phosphate kinase type I90 (PIPKI90), which is involved in the regulation of integrin activation, in Madin-Darby canine kidney cells, preferentially reversed the inactivation of integrin _vβ₃ at cell-cell adhesion sites and partially disrupted E-cadherin-based AJs. The activation of PIPKI is correlated with its phosphorylation state. The tyrosine phosphatase protein-tyrosine phosphatase µ (PTPµ) effectively dephosphorylated PIPKI and thus canceled the PIPKI-dependent activation of integrin _vβ₃ by blocking the interaction of integrin _vβ₃ with talin. Moreover, PTPµ associated with nectin, and its phosphatase activity was enhanced by the trans-interaction of nectin, leading to the decrease in PIPKI90 phosphorylation. Therefore, the trans-interaction of nectin essentially functions in the inactivation of integrin at AJs through the PTPµ-induced inactivation of PIPKI.

Received for publication, May 22, 2007 , and in revised form, September 20, 2007.

^* This work was supported by grants-in-aid for Scientific Research and for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (2006 and 2007). 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: Dept. of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan. Tel.: 81-78-382-5400; Fax: 81-78-382-5419; E-mail: ytakai{at}med.kobe-u.ac.jp.

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