BetaPix-enhanced p38 activation by Cdc42/Rac/PAK/MKK3/6-mediated pathway. Implication in the regulation of membrane ruffling.
betaPix (PAK-interacting exchange factor) is a recently identified guanine nucleotide exchange factor for Rho family small G protein Cdc42/Rac. The protein interacts with p21-activated protein kinase (PAK) through its SH3 domain. We examined the effect of betaPix on MAP kinase signaling and cytoskeletal rearrangement in NIH3T3 fibroblast cells. Overexpression of betaPix enhanced the activation of p38 in the absence of other stimuli and also induced translocation of p38 to the nucleus. This betaPix-induced p38 activation was blocked by coexpression of dominant-negative Cdc42/Rac or kinase-inactive PAK, indicating that the effect of betaPix on p38 is exerted through the Cdc42/Rac-PAK pathway and requires PAK kinase activity. The essential role of betaPix in growth factor-stimulated p38 activation was evidenced by the blocking of platelet-derived growth factor-induced p38 activation in the cells expressing betaPix SH3m (W43K) and betaPix DHm (L238R,L239R). In addition, SB203580, a p38 inhibitor, and kinase-inactive p38 (T180A,Y182F) blocked membrane ruffling induced by betaPix, suggesting that p38 might be involved in mediating betaPix-induced membrane ruffling. The results in this study suggest that betaPix might have a role in nuclear signaling, as well as in actin cytoskeleton regulation, and that some part of these cellular functions is possibly mediated by p38 MAP kinase.
Lee
S H
SH
School of Biological Sciences, Seoul National University, Seoul, 151-742, Republic of Korea.
Eom
M
M
Lee
S J
SJ
Kim
S
S
Park
H J
HJ
Park
D
D
D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000494:pharmacology*; D002462:Cell Membrane / Q000648:ultrastructure*; D002467:Cell Nucleus / Q000201:enzymology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000494:pharmacology*; D048371:MAP Kinase Kinase 3; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D054462:p21-Activated Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018909:src Homology Domains
C576607:Arhgef7 protein, mouse; D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D011505:Protein-Tyrosine Kinases; C515903:PAK1 protein, human; C429007:PAK6 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D020764:cdc42 GTP-Binding Protein