Phosphatidylinositol-4,5 bisphosphate produced by PIP5KIγ regulates gelsolin, actin assembly, and adhesion strength of N-cadherin junctions

T. Y. El Sayegh, P. D. Arora, K. Ling, C. Laschinger, P. A. Janmey, R. A. Anderson, C. A. McCulloch

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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-PLCδ 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 PIP5KIγ was spatially associated with N-cadherin-Fc beads. Association of PIP5KIγ with N-cadherin adhesions was in part dependent on the activation of RhoA. Transfection with catalytically inactive PIP5KIγ blocked the enrichment of PI(4,5)P 2 around beads. Catalytically inactive PIP5KIγ or a cell-permeant peptide that mimics and competes for the PI(4,5)P 2-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 more than twofold. Gelsolin null fibroblasts transfected with a gelsolin severing mutant containing an intact PI(4,5)P 2 binding region, demonstrated intercellular adhesion strength similar to wild-type transfected controls. We conclude that PIP5KIγ- 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.

Original languageEnglish (US)
Pages (from-to)3026-3038
Number of pages13
JournalMolecular biology of the cell
Volume18
Issue number8
DOIs
StatePublished - Aug 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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