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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Tyrosine phosphatase PTP regulates focal adhesion remodeling through Rac1 activation

¹Division of Respirology, Department of Medicine, and ⁴Canadian Institutes of Health Research Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, Toronto, Ontario, Canada; ²Cornell University, Ithaca, New York; and ³Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Submitted 10 August 2007 ; accepted in final form 18 January 2008

We characterized the role of protein tyrosine phosphatase (PTP)- in focal adhesion (FA) formation and remodeling using wild-type and PTP-deficient (PTP^–/–) cells. Compared with wild-type cells, spreading PTP^–/– fibroblasts displayed fewer leading edges and formed elongated -actinin-enriched FA at the cell periphery. These features suggest the presence of slowly remodeling cell adhesions and were phenocopied in human fibroblasts in which PTP was knocked down using short interfering RNA (siRNA) or in NIH-3T3 fibroblasts expressing catalytically inactive (C433S/C723S) PTP. Fluorescence recovery after photobleaching showed slower green fluorescence protein--actinin recovery in the FA of PTP^–/– than wild-type cells. These alterations correlated with reduced cell spreading, adhesion, and polarization and retarded contraction of extracellular matrices in PTP^–/– fibroblasts. Activation of Rac1 and its recruitment to FA during spreading were diminished in cells expressing C433S/C723S PTP. Rac1^–/– cells also displayed abnormally elongated and peripherally distributed FA that failed to remodel. Conversely, expression of constitutively active Rac1 restored normal FA remodeling in PTP^–/– cells. We conclude that PTP is required for remodeling of FA during cell spreading via a pathway involving Rac1.

cell spreading; integrins; extracellular matrix; actin cytoskeleton

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