Involvement of Nectin in Inactivation of Integrin αvβ3 after the Establishment of Cell-Cell Adhesion

Yasuhisa Sakamoto,Hisakazu Ogita,Hitomi Komura,Yoshimi Takai

doi:10.1074/jbc.m704195200

Yasuhisa Sakamoto, Hisakazu Ogita + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m704195200

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Abstract

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 alpha(v)beta(3) is critically necessary for this nectin-induced formation of AJs. However, after the establishment of AJs, integrin alpha(v)beta(3) becomes inactive and retains the association with nectin at AJs. The molecular mechanism of this dynamic regulation of integrin alpha(v)beta(3) during the formation of AJs remains unclear. We found here that the expression of phosphatidylinositol-phosphate kinase type Igamma90 (PIPKIgamma90), which is involved in the regulation of integrin activation, in Madin-Darby canine kidney cells, preferentially reversed the inactivation of integrin alpha(v)beta(3) at cell-cell adhesion sites and partially disrupted E-cadherin-based AJs. The activation of PIPKIgamma is correlated with its phosphorylation state. The tyrosine phosphatase protein-tyrosine phosphatase mu (PTPmu) effectively dephosphorylated PIPKIgamma and thus canceled the PIPKIgamma-dependent activation of integrin alpha(v)beta(3) by blocking the interaction of integrin alpha(v)beta(3) with talin. Moreover, PTPmu associated with nectin, and its phosphatase activity was enhanced by the trans-interaction of nectin, leading to the decrease in PIPKIgamma90 phosphorylation. Therefore, the trans-interaction of nectin essentially functions in the inactivation of integrin at AJs through the PTPmu-induced inactivation of PIPKIgamma.

Highlights

Integrin is a key cell-cell adhesion molecule at cell-matrix junctions and comprises heterodimers with ␣ and ␤ subunits [1]
After the establishment of adherens junctions (AJs), the high affinity form of integrin ␣v␤3 is converted into the low affinity form that continues to associate with nectin [17, 18]
After the achievement of AJs, the high affinity form of integrin ␣v␤3 is converted into the low affinity form that continues to localize at AJs

Summary

Nectin and Integrin Inactivation

During the nectin-induced formation of cadherin-based AJs, several intracellular signaling molecules including Rap, Cdc, and Rac small G proteins are activated, and actin cytoskeleton is reorganized by the trans-interaction of nectin in cooperation with the high affinity form of integrin ␣v␤3 (14 – 17). In this process, the activation of protein kinase C and FAK, downstream molecules of integrin ␣v␤3, is required [17, 18]. Based on these lines of evidence, we examined in this study how integrin ␣v␤3 is inactivated after the nectin-induced formation of AJs by exploring the phosphatase that suppresses the phosphorylation of PIPKI␥ and whether nectin associates with this phosphatase and regulates its phosphatase activity

EXPERIMENTAL PROCEDURES

RESULTS

The tyrosine phosphorylation of

DISCUSSION