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A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397
Qi Shi, and
David Boettiger *
Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Received for publication January 27, 2003.
Revision received May 7, 2003.
Accepted for publication July 1, 2003.
Monitoring Editor: Paul Matsudaira
The common model for integrin mediated signaling is based onintegrin clustering and the potential for that clustering torecruit signaling molecules including FAK and src. The clusteringmodel for transmembrane signaling originated with the analysisof the EGF receptor signaling and remains the predominant model.The roles for substrate-bound ligand and ligand occupancy inintegrin-mediated signaling are less clear. A kinetic modelwas established using HT1080 cells in which there was a linearrelationship between the strength of adhesion, the proportionof 51 integrin that could be chemically cross-linked, and thenumber of receptor-ligand bonds. This graded signal produceda similarly graded response measured by the level of specificphosphorylation of FAK Y397. FAK Y397 phosphorylation couldalso be induced by antibody bound to the substrate. In contrast,clustering of 51 on suspended cells with either antibody to1 or by clustering of soluble ligand bound to 51 induced thephosphorylation of FAK Y861 but not Y397. There were no differencesin signaling when activating antibodies were compared with blockingantibodies, presence or absence of ligand. Only tethering of51 to the substrate was required for induction of FAK Y397 phosphorylation.