The Caveolin genes: from cell biology to medicine

Abstract

Caveolae are vesicular organelles (50-100-nm in diameter) that are particularly abundant in cells of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes and fibroblasts. In these cell types, caveolae function both in protein trafficking and signal transduction, as well as in cholesterol homeostasis. Caveolins are the structural proteins that are both necessary and sufficient for the formation of caveolae membrane domains. Caveolins 1 and 2 are co-expressed in most cell types, while the expression of caveolin-3 is muscle-specific. Thus, endothelial cells and fibroblasts are rich in caveolins 1 and 2, while cardiac myocytes and skeletal muscle fibers express caveolin-3. In contrast, smooth muscle cells express all three caveolins (Cav-1, -2, and -3). Mechanistically, caveolins interact with a variety of downstream signaling molecules, including Src-family tyrosine kinases, p42/44 mitogen activated protein (MAP) kinase, and endothelial nitric oxide synthase (eNOS), and hold these signal transducers in the inactive conformation until activation by an appropriate stimulus. In many ways, caveolins serve both to compartmentalize and regulate signaling. Recent studies using caveolin-deficient mouse models dramatically show that caveolae and caveolins play a prominent role in various human patho-biological conditions, especially those related to the cardiovascular system. These disease phenotypes include: atherosclerosis, cardiac hypertrophy, cardiomyopathy, pulmonary hypertension, and neointimal hyperplasia (smooth muscle cell proliferation). In addition, caveolins play a significant role in other disease phenotypes, such as cancer, diabetes, bladder dysfunction, and muscular dystrophy, as we discuss in this review. Thus, caveolin-deficient mice will serve as important new animal models to dissect the intricate role of caveolae and caveolins in the pathogenesis of human diseases.

Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-α following ozone inhalation

“…We next analyzed the effects of ozone inhalation on expression of Cav-1, a membrane scaffolding protein known to negatively regulate PI3K and p44/42 MAPK (Williams and Lisanti, 2004;Schwencke et al, 2006). Western blot analysis revealed that alveolar macrophages from air exposed wild type mice constitutively expressed Cav-1 (Fig.…”

“…We found that macrophages from transgenic mice with a targeted disruption of the gene for TNFα were unable to generate reactive nitrogen intermediates and that these mice were protected from ozone toxicity. This was associated with a marked attenuation of ozone-induced activation of PI3K/PKB and p44/42 MAPK and suppression of caveolin-1 (Cav-1), a negative regulator of TNFα signaling (Williams and Lisanti, 2004). These findings are novel and may lead to the identification of new targets for therapeutic intervention aimed at regulating lung inflammation induced by pulmonary irritants.…”

Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury

“…There are three known isoforms of caveolin: caveolin-1, caveolin-2 and caveolin-3 [9], each of which has scaffolding domains that interact with signaling molecules [10,11]. Cardiac myocytes (CM) express the muscle-specific isoform caveolin-3 [12] while other cell types in the heart express caveolin-1 and -2.…”

Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance

“…The caveolins serve as membrane scaffolding proteins that compartmentalise various signalling molecules within discrete domains at the plasmalemma, termed caveolae [12]. Specifically, caveolin-1 is known to generally repress the inherent kinase activity of a number of proto-oncogenes through binding of the kinase catalytic regions to a contiguous twenty amino acid motif situated within the N-terminus of the caveolin-1 molecule, termed the caveolin scaffolding domain [13].…”