Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42.
Efficient chemotaxis requires directional sensing and cell polarization. We describe a signaling mechanism involving G beta gamma, PAK-associated guanine nucleotide exchange factor (PIX alpha), Cdc42, and p21-activated kinase (PAK) 1. This pathway is utilized by chemoattractants to regulate directional sensing and directional migration of myeloid cells. Our results suggest that G beta gamma binds PAK1 and, via PAK-associated PIX alpha, activates Cdc42, which in turn activates PAK1. Thus, in this pathway, PAK1 is not only an effector for Cdc42, but it also functions as a scaffold protein required for Cdc42 activation. This G beta gamma-PAK1/PIX alpha/Cdc42 pathway is essential for the localization of F-actin formation to the leading edge, the exclusion of PTEN from the leading edge, directional sensing, and the persistent directional migration of chemotactic leukocytes. Although ligand-induced production of PIP(3) is not required for activation of this pathway, PIP(3) appears to localize the activation of Cdc42 by the pathway.
Li
Zhong
Z
Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Hannigan
Michael
M
Mo
Zhicheng
Z
Liu
Bo
B
Lu
Wei
W
Wu
Yue
Y
Smrcka
Alan V
AV
Wu
Guanqing
G
Li
Lin
L
Liu
Mingyao
M
Huang
Chi-Kuang
CK
Wu
Dianqing
D
D000199:Actins / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D016764:Cell Polarity / Q000187:drug effects; D002633:Chemotaxis; D002522:Chlorocebus aethiops; D015936:Complement C5a / Q000494:pharmacology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; D015936:Complement C5a; D020662:Guanine Nucleotide Exchange Factors; D020962:Heterotrimeric GTP-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D020764:cdc42 GTP-Binding Protein