Requirement of caveolae microdomains in extracellular signal-regulated kinase and focal adhesion kinase activation induced by endothelin-1 in primaryastrocytes

Endothelin-1 (ET-1) mitogenic activity in astrocytes is mediated by the act ivation of the extracellular signal-regulated kinase (ERK) pathway together with the Rho-dependent activation of the focal adhesion kinase (FAK) pathw ay. To clarify the mechanisms responsible for the coordinate activation of both pathways in the ET-I signal propagation, the involvement of caveolae m icrodomains, suggested to play a role in signal transduction, was evaluated . In this study, it is reported that caveolae of primary astrocytes are enr iched in endothelin receptor (ETB-R). Furthermore, signaling molecules such as the adaptor proteins Shc and Grb2, and the small G protein Rho, also re side within these microdomains, Selective disassembly of caveolae by filipi n III impairs the ET-1-induced tyrosine phosphorylation of proteins includi ng ERK and FAK. In agreement with these observations, astrocytes pretreated with filipin III also failed to form stress fibers and focal adhesions and did not undergo the associated morphological changes in response to ET-I. This study reveals that structural integrity of caveolae is necessary for t he adhesion-dependent mitogenic signals induced by ET-I in astrocytes, thro ugh compartmentation of ETB-R with the upstream signaling molecules of the ERK and FAK pathways.