Endothelin 1 stimulates beta1Pix-dependent activation of Cdc42 through the G(salpha) pathway. Exp Biol Med (Maywood) 2006 Jun;231(6):761-5
Date
06/03/2006Pubmed ID
16740995Scopus ID
2-s2.0-33744920554 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
Beta1Pix (PAK-interacting exchange factor) is a recently identified guanine nucleotide exchange factor (GEF) for the Rho family small G protein Cdc42/Rac. On stimulation with extracellular signals, GEFs induce the exchange of guanosine diphosphate to guanosine triphosphate, resulting in the activation of the small guanosine 5C-triphosphatases. This activation enables the signal to propagate to downstream effectors. Herein, we show that G(salpha) stimulation by cholera toxin increased Cdc42 activation by endothelin-1 (ET-1), whereas pertussis toxin had no effect. H-89, a protein kinase A (PKA) inhibitor, strongly inhibited Cdc42 activation by ET-1. Moreover, the overexpression of beta1Pix enhanced ET-1-induced Cdc42 activation. The essential role of beta1Pix in ET-1-induced Cdc42 activation was evidenced by the blocking of Cdc42 activation in cells expressing beta1Pix mutant lacking the ability to bind PAK (beta1Pix SH3m[W43K]) or mutant lacking GEF activity (beta1PixdeltaDH). The overexpression of mutant lacking the pleckstrin homology domain beta1PixdeltaPH, which is unable to bind phospholipids, had no effect on Cdc42 activation. These results demonstrate that beta1Pix, along with PKA, plays a crucial role in the regulation of Cdc42 activation by ET-1.
Author List
Chahdi A, Sorokin AAuthor
Andrey Sorokin PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell Cycle ProteinsCell Line, Transformed
Cell Transformation, Viral
Cholera Toxin
Endothelin-1
GTP-Binding Protein alpha Subunits, Gs
Guanine Nucleotide Exchange Factors
Humans
Mesangial Cells
Rho Guanine Nucleotide Exchange Factors
cdc42 GTP-Binding Protein
