Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis.
Activation of the hepatocyte growth factor (HGF) receptor in epithelial cells results in lamellipodia protrusion, spreading, migration, and tubule formation. We have previously reported that these morphogenic effects are dependent on MAPK activation at focal adhesions. In the present study we demonstrate that activated ERK phosphorylates paxillin on serine 83 and that mutation of this site eliminates HGF-stimulated increased association of paxillin and FAK in subconfluent cells. Failure to activate FAK at focal adhesions results in a loss of FAK-PI 3-kinase association and the marked reduction of Rac activation after HGF stimulation. Expression of paxillin mutants that disrupt ERK association or phosphorylation inhibits HGF-induced cell spreading, migration, and tubulogenesis. These data demonstrate that the paxillin-MAPK complex serves as a central regulator of HGF-stimulated FAK and Rac activation in the vicinity of focal adhesions, thus promoting the rapid focal adhesion turnover and lamellipodia extension that are required for migratory and tubulogenic responses.
Ishibe
Shuta
S
Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT 06520, USA.
Joly
Dominique
D
Liu
Zhen-Xiang
ZX
Cantley
Lloyd G
LG
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D051379:Mice; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D003598:Cytoskeletal Proteins; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; D012694:Serine; D017228:Hepatocyte Growth Factor; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins