Hepatocyte Growth Factor stimulated cell scattering requires ERK and Cdc42-dependent tight junction disassembly.
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.
Togawa
Akashi
A
Section of Nephrology, Yale University School of Medicine, New Haven, CT 06520, USA. togawa_akashi@yahoo.co.jp
Sfakianos
Jeffery
J
Ishibe
Shuta
S
Suzuki
Sayuri
S
Fujigaki
Yoshihide
Y
Kitagawa
Masatoshi
M
Mellman
Ira
I
Cantley
Lloyd G
LG
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D064546:Protein Kinase C beta; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C499657:PARD6A protein, human; D017228:Hepatocyte Growth Factor; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048049:Extracellular Signal-Regulated MAP Kinases; D020764:cdc42 GTP-Binding Protein