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The γ-Parvin-Integrin-Linked Kinase Complex Is Critically Involved in Leukocyte-Substrate Interaction1

Leukocyte extravasation is an important step of inflammation, in which integrins have been demonstrated to play an essential role by mediating the interaction of leukocytes with the vascular endothelium and the subendothelial extracellular matrix. Previously, we identified an integrin-linked kinase (ILK)-binding protein affixin (β-parvin), which links initial integrin signals to rapid actin reorganization, and thus plays critical roles in fibroblast migration. In this study, we demonstrate that γ-parvin, one of three mammalian parvin family members, is specifically expressed in several lymphoid and monocytic cell lines in a complementary manner to affixin. Like affixin, γ-parvin directly associates with ILK through its CH2 domain and colocalizes with ILK at focal adhesions as well as the leading edge of PMA-stimulated U937 cells plated on fibronectin. The overexpression of the C-terminal fragment containing CH2 domain or the depletion of γ-parvin by RNA interference inhibits the substrate adhesion of MCP-1-stimulated U937 cells and the spreading of PMA-stimulated U937 cells on fibronectin. Interestingly, the overexpression of the CH2 fragment or the γ-parvin RNA interference also disrupts the asymmetric distribution of PTEN and F-actin observed at the very early stage of cell spreading, suggesting that the ILK-γ-parvin complex is essential for the establishment of cell polarity required for leukocyte migration. Taken together with the results that γ-parvin could form a complex with some important cytoskeletal proteins, such as αPIX, α-actinin, and paxillin as demonstrated for affixin and actopaxin (α-parvin), the results in this study suggest that the ILK-γ-parvin complex is critically involved in the initial integrin signaling for leukocyte migration.