p190-RhoGAP as an integral component of the Tiam1/Rac1-induced downregulation of Rho.
The Rho family of small GTPases plays a central role in intracellular signal transduction, particularly in reorganization of the actin cytoskeleton. Rho activity induces cell contractility, whereas Rac promotes cellular protrusion, which counteracts Rho signaling. In this regard, the reciprocal balance between these GTPases determines cell morphology and migratory behavior. Here we demonstrate that Tiam1/Rac1 signaling is able to antagonize Rho activity directly at the GTPase level in COS-7 cells. p190-RhoGAP plays a central regulatory role in this signaling pathway. Interfering with its activation by Src-kinase-dependent tyrosine phosphorylation or its recruitment to the membrane through interaction with the SH2 domains of p120-RasGAP blocks the Tiam1-mediated rapid downregulation of Rho. This process is mediated by Rac1, but not by Rac2 or Rac3 isoforms. Our data provide evidence for a biochemical pathway of the reciprocal regulation of two related small GTPases, which are key elements in cell migration.
Max Planck Institute of Molecular Physiology, Department of Structural Biology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany. reza.ahmadian@mpi-dortmund.mpg.de
Ulrike
U
Herbrand
Mohammad Reza
MR
Ahmadian
D000199:Actins / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement; D002522:Chlorocebus aethiops; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D020729:p120 GTPase Activating Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D000199:Actins; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D020729:p120 GTPase Activating Protein; D014443:Tyrosine; D019061:src-Family Kinases; D020558:GTP Phosphohydrolases; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins