Hepatocyte Growth Factor stimulated cell scattering requires ERK and Cdc42-dependent tight junction disassembly

Biochem Biophys Res Commun. 2010 Sep 17;400(2):271-7. doi: 10.1016/j.bbrc.2010.08.060. Epub 2010 Aug 20.

Abstract

The mechanism by which Hepatocyte Growth Factor (HGF) induces tight junction disassembly prior to cell scattering is largely unknown. Here, we show that HGF stimulates rapid loss of the TJ assembly protein Par6 from the TJ in an Erk-dependent manner. Erk activation by HGF is found to mediate the interaction of Par6 with GTP-loaded Cdc42. The Cdc42 GTPase activating protein cdGAP is shown to interact with Pkcζ at baseline and prevent Par6-Cdc42 association. Erk, by phosphorylating cdGAP at threonine776, can inhibit the GAP activity, thereby increasing Par6-Cdc42 association and TJ disassembly. Our findings reveal a novel pathway for regulating HGF signaling to the Par proteins through Erk-cdGAP, resulting in TJ disassembly and cell scattering.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Dogs
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Hepatocyte Growth Factor / pharmacology
  • Hepatocyte Growth Factor / physiology*
  • Humans
  • Phosphorylation
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Protein Kinase C beta
  • Tight Junctions / drug effects
  • Tight Junctions / physiology*
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • PARD6A protein, human
  • Hepatocyte Growth Factor
  • Protein Kinase C
  • Protein Kinase C beta
  • Extracellular Signal-Regulated MAP Kinases
  • cdc42 GTP-Binding Protein