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RPTP- acts as a transducer of mechanical force on _v/ß₃-integrin–cytoskeleton linkages

¹ Department of Biological Sciences, Columbia University, New York, NY 10027
² Department of Pharmacology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016

Address correspondence to Michael P. Sheetz, Dept. of Biological Sciences, P.O. Box 2408, Columbia University, Sherman Fairchild Center, Rm. 713, 1212 Amsterdam Ave., New York, NY 10027. Tel.: (212) 854-4857. Fax: (212) 854-6399. E-mail: ms2001{at}columbia.edu

Cell motility on ECM critically depends on the cellular response to force from the matrix. We find that force-dependent reinforcement of _v/ß₃-integrin–mediated cell–matrix connections requires the receptor-like tyrosine phosphatase (RPTP). RPTP colocalizes with _v-integrins at the leading edge during early spreading, and coimmunoprecipitates with _v-integrins during spreading on fibronectin and vitronectin. RPTP-dependent activation of Src family kinases, in particular activation of Fyn, is required for the force-dependent formation of focal complexes and strengthening of _v/ß₃-integrin–cytoskeleton connections during the initial phase of ECM contact. These observations indicate that Src family kinases have distinct functions during adhesion site assembly, and that RPTP is an early component in force-dependent signal transduction pathways leading to the assembly of focal complexes on both fibronectin and vitronectin.

Key Words: phosphatase; force; src family kinases; focal contact; mechanotransduction

^* Abbreviations used in this paper: CSK, c-terminal Src kinase; FN, fibronectin; GPen, GPenGRGDSPCA; LA, laminin; MSD, mean square displacement; RPTP, receptor-like protein tyrosine phosphatase ; SFK, Src family kinase; VN, vitronectin.

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