Phosphatidylinositol 3'-kinase signalling supports cell height in established epithelial monolayers

J Mol Histol. 2009 Oct;40(5-6):395-405. doi: 10.1007/s10735-010-9253-y. Epub 2010 Feb 16.

Abstract

Cell-cell interactions influence epithelial morphogenesis through an interplay between cell adhesion, trafficking and the cytoskeleton. These cellular processes are coordinated, often by cell signals found at cell-cell contacts. One such contact-based signal is the phosphatidylinositol 3'-kinase (PI3-kinase; PI3K) pathway. PI3-kinase is best understood for its role in mitogenic signalling, where it regulates cell survival, proliferation and differentiation. Its precise morphogenetic impacts in epithelia are, in contrast, less well-understood. Using phosphoinositide-specific biosensors we confirmed that E-cadherin-based cell-cell contacts are enriched in PIP(3), the principal product of PI3-kinase. We then used pharmacologic inhibitors to assess the morphogenetic impact of PI3-kinase in MDCK and MCF7 monolayers. We found that inhibiting PI3-kinase caused a reduction in epithelial cell height that was reversible upon removal of the drugs. This was not attributable to changes in E-cadherin expression or homophilic adhesion. Nor were there detectable changes in cell polarity. While Myosin II has been implicated in regulating keratinocyte height, we found no effect of PI3-kinase inhibition on apparent Myosin II activity; nor did direct inhibition of Myosin II alter epithelial height. Instead, in pursuing signalling pathways downstream of PI3-kinase we found that blocking Rac signalling, but not mTOR, reduced epithelial cell height, as did PI3-kinase inhibition. Overall, our findings suggest that PI3-kinase exerts a major morphogenetic impact in simple cultured epithelia through preservation of cell height. This is independent of potential effects on adhesion or polarity, but may occur through PI3-kinase-stimulated Rac signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Cell Adhesion / drug effects
  • Cell Communication / drug effects
  • Cell Line
  • Cell Polarity / drug effects
  • Cell Size* / drug effects
  • Dogs
  • Epithelial Cells / cytology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Myosin Type II / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Transport / drug effects
  • Signal Transduction* / drug effects
  • TOR Serine-Threonine Kinases
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Cadherins
  • Intracellular Signaling Peptides and Proteins
  • Phosphatidylinositol Phosphates
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • phosphatidylinositol 3,4,5-triphosphate
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • Myosin Type II
  • rac1 GTP-Binding Protein