Caveolins muscle their way into the regulation of cell differentiation, development, and function. Focus on "Muscle-specific interaction of caveolin isoforms: differential complex formation between caveolins in fibroblastic vs. muscle cells.".

SINCE THEIR INITIAL CHARACTERIZATION in the early 1990s, the functions ascribed to caveolin proteins have steadily increased in complexity and sophistication. Caveolins were initially identified as the main component of the “coat” of caveolae, vesicles that were originally described in the 1950s (22). Caveolae were initially considered to be vesicular structures that mediated transcytosis of macromolecules; caveolins were thus viewed as structural proteins that aided formation of the vesicle. By the mid-1990s, caveolae and their “siblings,” lipid rafts, rapidly became appreciated as “hot spots” for plasmalemmal signaling, with a newly recognized function as organizational or scaffolding proteins that attract and retain certain signaling moieties in efficient complexes. However, in recent years, evidence has steadily mounted to support the notion that caveolins are much more than simply structural components of vesicles or docking sites for signaling molecules. In fact, caveolins are now acknowledged to be critical regulators of several signaling pathways that control cell development, differentiation, and proliferation. Caveolar vesicles, 50- to 100-nm flasklike indentations (“little caves”), can be morphologically identified in the plasma membrane of cells that express caveolin (1). Caveolae, which are expressed only by certain cells, have a lipid composition similar to that of lipid rafts (and can be considered subsets of lipid rafts), which are expressed by all mammalian cells (12). Three isoforms of caveolin have been identified, caveolin-1 (Cav-1), caveolin-2 (Cav-2), and caveolin-3 or M-caveolin (Cav-3) (10, 25, 32, 34). Cav-1 is the most widely expressed and well studied of the caveolins. Although structurally unique, Cav-3 is specific to striated muscle but is similar to Cav-1 in that both isoforms contain a scaffolding domain near their amino termini that can interact with a number of signaling proteins and both can induce caveolar biosynthesis. Cav-2 is the “black sheep” of the caveolin family because it appears to exist only as a heterooligomer with Cav-1 or Cav-3 and does not induce caveolar biosynthesis on its own (13, 20, 23–25). The biology of caveolin proteins has been reviewed in detail elsewhere (15, 21, 35), as has the role of caveolae as microdomains that compartmentalize plasmalemmal signaling (8, 16, 17, 28). As Cav-1 began to be intensively studied, it became clear that not only did it bind numerous signaling proteins via its amino-terminal scaffolding domain but also that this region could inhibit the activity of many of these binding partners (5, 27). Examples include endothelial nitric oxide synthase, epidermal growth factor receptor, Src tyrosine kinases, Ras, protein kinase C, G protein receptor kinase, and adenylyl cyclase. Recent data also demonstrate that Cav-1 is not restricted to the caveolar coat, but can be found in the cytosol and other cellular organelles in striated muscle and other cell types (4, 14). Such mechanistic studies helped provide a strong rationale for examining the physiology of caveolins using transgenic and knockout mice (21). Those more recent in vivo investigations have revealed even more complex and diverse roles for the caveolins than had been previously known. Cav-1 alters lipid homeostasis and regulates mitogenic pathways that influence cell proliferation, particularly in the lung and vasculature (6, 19). Cav-3 is central to normal skeletal muscle differentiation and function, with Cav-3 knockout mice displaying atypical muscle fibers and immature T tubules (7). Taken together, these studies have translated earlier molecular observations of caveolin function to illustrations of the impact Cav-1 and Cav-3 on cellular development, differentiation, and homeostasis. Similar studies of Cav-2 were not expected to be as dramatic. Surprisingly, Cav-2-knockout animals display a profound pulmonary phenotype, suggesting a key role for this caveolin in lung cell mitogenesis (20). This finding, along with data showing that Cav-2 is a necessary complement to Cav-1 in the lung (13), may signal a resurgence in appreciation for this more poorly studied member of the caveolin family. There is now even greater impetus for expending effort in studies of Cav-2. In this issue, Capozza and colleagues (Ref. 3, see p. C677 in this issue) report that Cav-1, Cav-2, and Cav-3 can interact to form oligomers in striated muscle, but in fibroblasts Cav-2 and Cav-3 do not interact. These studies build on reports by Rybin et al. (23), who examined cardiac myocytes and first demonstrated that Cav-2 and Cav-3 can interact, and Woodman et al. (36), who examined bladder smooth muscle and also observed oligomerization of all three caveolin isoforms. Together, these reports alter our views of the role of caveolin isoforms, particularly Cav-2, in muscle physiology. Capozza et al. (3) report that Cav-2 must be coexpressed with Cav-1 in fibroblasts to be localized in lipid rafts or caveolae or to be significantly expressed. These observations are consistent with previous reports from this group and others. Expression of Cav-3 did not rescue expression of Cav-2 and did not result in the formation of Cav-1/Cav-3 heterooligomers. These findings in fibroblasts presumably relate to a similar interaction of caveolins in other nonmuscle cells. However, in undifferentiated L6 myoblast cells that