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MBC in Press, published online ahead of print May 30, 2007
Mol. Biol. Cell 10.1091/mbc.E06-12-1159

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Submitted on December 29, 2006
Revised on April 16, 2007
Accepted on May 22, 2007

Phosphatidylinositol-4,5 Bisphosphate Produced by PIP5KI{gamma} Regulates Gelsolin, Actin Assembly, and Adhesion Strength of N-Cadherin Junctions

T. Y. El Sayegh,* P. D. Arora,* K. Ling,{dagger} C. Laschinger,* P. A. Janmey,{ddagger} R. A. Anderson,{dagger} and C. A. McCulloch*

*CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada M5S 3E2; {dagger}Department of Pharmacology, University of Wisconsin Medical School, Madison, WI 53706; {ddagger}Institute for Medicine and Engineering, Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104

Monitoring Editor: Asma Nusrat

Phosphoinositides regulate several actin binding proteins but their role at intercellular adhesions has not been defined. We found that phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) was generated at sites of N-cadherin-mediated intercellular adhesion and was a critical regulator of intercellular adhesion strength. Immunostaining for PI(4,5)P2 or transfection with GFP-PH-PLC{delta} showed that PI(4,5)P2 was enriched at sites of N-cadherin adhesions and this enrichment required activated Rac1. Isoform-specific immunostaining for type I phosphatidylinositol 4-phosphate 5 kinase (PIP5KI) showed that PIP5KI{gamma} was spatially associated with Ncad-Fc beads. Association of PIP5KI{gamma} with N-cadherin adhesions was in part dependent on the activation of RhoA. Transfection with catalytically inactive PIP5KI{gamma} blocked the enrichment of PI(4,5)P2 around beads. Catalytically inactive PIP5KI{gamma} or a cell-permeant peptide that mimics and competes for the PI(4,5)P2 binding region of the actin binding protein gelsolin inhibited incorporation of actin monomers in response to N-cadherin ligation and reduced intercellular adhesion strength by >2-fold. Gelsolin null fibroblasts transfected with a gelsolin severing mutant containing an intact PI(4,5)P2 binding region, demonstrated intercellular adhesion strength similar to wild-type transfected controls. We conclude that PIP5KI{gamma}-mediated generation of PI(4,5)P2 at sites of N-cadherin contacts regulates intercellular adhesion strength, an effect due in part to PI(4,5)P2 mediated regulation of gelsolin.

Address correspondence to: T. Y. El Sayegh (t.elsayegh{at}utoronto.ca)






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