Caveolae Required for Stretch Response

Abstract

Cells respond to stretch by activating various intracellular signaling pathways that result in rearrangement of the cytoskeleton and alterations in gene expression. Kawamura et al. investigated the role of a specialized membrane microdomain--caveolae, which are defined by the biochemical characteristics and the presence of the protein caveolin--in regulating signals that control the actin cytoskeleton and translocation of signaling proteins into the nucleus. In neonatal rat ventricular cardiomyocytes, caveolae are enriched in caveolin-3, a specific isoform of caveolin, and in the guanosine triphosphatases (GTPases) RhoA and Rac1, which are both implicated in regulating the actin cytoskeleton. In response to biaxial stretch, RhoA and Rac1 GTPase activity was stimulated and these proteins were redistributed out of caveolin-positive membranes. When caveolae were disrupted with methyl β-cyclodextrin (MβCD), then RhoA and Rac1 were no longer associated with caveolin, and activation of these two GTPases by stretch was impaired. Activation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) by stretch was not inhibited by MβCD treatment; however, translocation to the nucleus was blocked. Stretch of MβCD-treated cells did not promote organization of the actin cytoskeleton as seen in control cells. Treatment of the MβCD-treated cells with the actin polymerizer jasplakinolide promoted nuclear translocation of phosphorylated ERK1/2. The actin depolymerizer cytochalasin-D prevented translocation of phosphorylated ERK1/2 in response to stretch. The authors propose that cells subjected to stress receive a signal through their caveolae that activates RhoA and Rac1, leading to actin reorganization, and another signal most likely mediated by integrins that activates ERKs. These two pathways converge at the point of nuclear translocation of ERKs, such that ERKs are activated in the absence of caveolae, but nuclear translocation requires the cytoskeletal rearrangements that are dependent on caveolae. S. Kawamura, S. Miyamoto, J. H. Brown, Initiation and transduction of stretch-induced RhoA and Rac1 activation through caveolae: Cytoskeletal regulation of ERK translocation. J. Biol. Chem. 278 , 31111-31117 (2003). [Abstract] [Full Text]