Requirement of caveolae microdomains in extracellular signal-regulated kinase and focal adhesion kinase activation induced by endothelin-1 in primary astrocytes.
Endothelin-1 (ET-1) mitogenic activity in astrocytes is mediated by the activation of the extracellular signal-regulated kinase (ERK) pathway together with the Rho-dependent activation of the focal adhesion kinase (FAK) pathway. To clarify the mechanisms responsible for the coordinate activation of both pathways in the ET-1 signal propagation, the involvement of caveolae microdomains, suggested to play a role in signal transduction, was evaluated. In this study, it is reported that caveolae of primary astrocytes are enriched in endothelin receptor (ETB-R). Furthermore, signaling molecules such as the adaptor proteins Shc and Grb2, and the small G protein Rho, also reside within these microdomains. Selective disassembly of caveolae by filipin III impairs the ET-1-induced tyrosine phosphorylation of proteins including 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-1. This study reveals that structural integrity of caveolae is necessary for the adhesion-dependent mitogenic signals induced by ET-1 in astrocytes, through compartmentation of ETB-R with the upstream signaling molecules of the ERK and FAK pathways.
Teixeira
A
A
CNRS UPR 0415, Université Paris VII, Institut Cochin de Génétique Moléculaire, Paris, France.
Chaverot
N
N
Schröder
C
C
Strosberg
A D
AD
Couraud
P O
PO
Cazaubon
S
S
D000199:Actins / Q000032:analysis; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001253:Astrocytes / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D051242:Caveolin 1; D022461:Caveolins; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002451:Cell Compartmentation / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000201:enzymology; D005372:Filipin / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008565:Membrane Proteins / Q000032:analysis; D019950:Mitogen-Activated Protein Kinase 1; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D000199:Actins; D000900:Anti-Bacterial Agents; D051242:Caveolin 1; D022461:Caveolins; D015815:Cell Adhesion Molecules; D019332:Endothelin-1; D008565:Membrane Proteins; D014443:Tyrosine; D005372:Filipin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1