Essential role of CIB1 in regulating PAK1 activation and cell migration.
p21-activated kinases (PAKs) regulate many cellular processes, including cytoskeletal rearrangement and cell migration. In this study, we report a direct and specific interaction of PAK1 with a 22-kD Ca2+-binding protein, CIB1, which results in PAK1 activation both in vitro and in vivo. CIB1 binds to PAK1 within discrete regions surrounding the inhibitory switch domain in a calcium-dependent manner, providing a potential mechanism of CIB1-induced PAK1 activation. CIB1 overexpression significantly decreases cell migration on fibronectin as a result of a PAK1-and LIM kinase-dependent increase in cofilin phosphorylation. Conversely, the RNA interference-mediated depletion of CIB1 increases cell migration and reduces normal adhesion-induced PAK1 activation and cofilin phosphorylation. Together, these results demonstrate that endogenous CIB1 is required for regulated adhesion-induced PAK1 activation and preferentially induces a PAK1-dependent pathway that can negatively regulate cell migration. These results point to CIB1 as a key regulator of PAK1 activation and signaling.
Leisner
Tina M
TM
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Liu
Mingjuan
M
Jaffer
Zahara M
ZM
Chernoff
Jonathan
J
Parise
Leslie V
LV
D051339:Actin Depolymerizing Factors; D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D051339:Actin Depolymerizing Factors; C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D005353:Fibronectins; D008840:Microfilament Proteins; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D002118:Calcium