Faculty Collaboration Database

The role of beta(1)Pix/caveolin-1 interaction in endothelin signaling through Galpha subunits. Biochem Biophys Res Commun 2010 Jan 15;391(3):1330-5

Date

12/23/2009

Pubmed ID

20026011

Pubmed Central ID

PMC2813521

DOI

10.1016/j.bbrc.2009.12.041

Scopus ID

2-s2.0-73949128415 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

Endothelin-1 (ET-1) is a potent mitogen that transmits signals through its cognate G protein-coupled receptors to stimulate extracellular signal-regulated kinase Erk1/2. Endothelin-1 receptors (ET-Rs) are known to interact with caveolin-1 and co-localize in caveolae which integrate different receptor and signaling proteins. We have recently shown that beta(1)Pix binds specifically to ET-Rs. Here, we show that beta(1)Pix binding to caveolin-1 is dependent on heterotrimeric G proteins activation state. beta(1)Pix interaction with different G proteins is increased in the presence of the G protein activator AMF. Moreover, extraction of cholesterol with methyl-beta-cyclodextrin disrupts the binding of beta(1)Pix to Galpha(q), Galpha(12) and phospho-Erk1/2 but not the binding of beta(1)Pix to G(beta1). The disruption of beta(1)Pix dimerization strongly reduced the binding of caveolin-1, Galpha(q) and Galpha(12). Constitutively active mutants of Galpha(q) and Galpha(12) increased Cdc42 activation when co-expressed with beta(1)Pix but not in the presence of beta(1)Pix dimerization deficient mutant beta(1)PixDelta (602-611). ET-1 stimulation increased the binding of phosphorylated Erk1/2 to beta(1)Pix but not to beta(1)PixDelta (602-611). RGS3 decreased ET-1-induced Cdc42 activation. These results strongly suggest that the activation of ET-Rs leads to the compartmentalization and the binding of Galpha(q) to beta(1)Pix in caveolae, where dimeric beta(1)Pix acts as platform to facilitate the binding and the activation of Erk1/2.

Author List

Chahdi A, Sorokin A

Author

Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Caveolin 1
Cells, Cultured
Endothelin-1
GTP-Binding Protein alpha Subunits, G12-G13
GTP-Binding Protein alpha Subunits, Gq-G11
GTP-Binding Proteins
GTPase-Activating Proteins
Guanine Nucleotide Exchange Factors
Humans
Mitogen-Activated Protein Kinase 3
Protein Multimerization
RGS Proteins
Rho Guanine Nucleotide Exchange Factors
Signal Transduction
cdc42 GTP-Binding Protein