Endothelin-1 induces p66Shc activation through EGF receptor transactivation: Role of beta(1)Pix/Galpha(i3) interaction. Cell Signal 2010 Feb;22(2):325-9
Date
10/07/2009Pubmed ID
19804820Pubmed Central ID
PMC2788086DOI
10.1016/j.cellsig.2009.09.039Scopus ID
2-s2.0-70450222306 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
Endothelin-1 (ET-1) is a vasoconstrictor peptide known to be a potent mitogen for glomerular mesangial cells. We have shown that ET-1 stimulates the adaptor protein p66Shc through Rac/Cdc42 guanine nucleotide exchange factor beta(1)Pix. In this study, we demonstrate that ET-1-induced serine phosphorylation of p66Shc is mediated through Galpha(i3). Pertussis toxin treatment of cells induced a significant decrease in the interaction between beta(1)Pix and ET(A)-R, and an increase in the binding of Galpha(i3) and G(beta1) to beta(1)Pix. Activation of heterotrimeric G proteins by AlF(4)(-) resulted in an increase of Galpha(i3) binding to beta(1)Pix, which was significantly disrupted in cells expressing beta(1)Pix dimerization deficient mutant, beta(1)PixDelta (602-611). In cells expressing beta(1)PixDelta (602-611), ET-1-induced p66Shc activation was also significantly decreased. Specific inhibition of EGF receptor by AG1478 blocked ET-1-induced p66Shc activation and the binding of p66Shc and Galpha(i3) to beta(1)Pix. Inhibition of Erk1/2 blocked p66Shc activation induced by ET-1. Altogether, our results indicate that ET-1 activates p66Shc through EGF receptor transactivation, leading to the activation of Galpha(i3), beta(1)Pix and Erk1/2.
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
Cells, CulturedEndothelin-1
ErbB Receptors
GTP-Binding Protein alpha Subunits, Gi-Go
Guanine Nucleotide Exchange Factors
Humans
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Pertussis Toxin
Phosphorylation
Rho Guanine Nucleotide Exchange Factors
Shc Signaling Adaptor Proteins