Cell. Signal. Vol. 10, No. 7, pp. 457–463, 1998 ISSN 0898-6568/98 $19.00 Copyright  1998 Elsevier Science Inc. PII S0898-6568(98)00007-2 TOPICAL REVIEW Crowded Little Caves: Structure and Function of Caveolae Amnon Schlegel,† Daniela Volonte ´,† Jeffrey A. Engelman,† Ferruccio Galbiati,† Pravina Mehta,† Xiao-Lan Zhang,† Philipp E. Scherer‡ and Michael P. Lisanti†* †Department of Molecular Pharmacology, and ‡Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA ABSTRACT. Caveolae are small vesicular invaginations of the cell membrane. It is within this organelle that cells perform transcytosis, potocytosis and signal transduction. These “little caves” are composed of a mixture of lipids and proteins unlike those found in the plasma membrane proper. The chief structural proteins of caveolae are caveolins. To date, three caveolins (Cav-1, -2 and -3) with unique tissue distributions have been identified. Caveolins form a scaffold onto which many signalling molecules can assemble, to generate pre-assembled signalling complexes. In addition to concentrating these signal transducers within a distinct region of the plasma membrane, caveolin binding may functionally regulate the activation state of caveolae-associated signalling molecules. cell signal 10;7:457–463, 1998.  1998 Elsevier Science Inc. KEY WORDS. Caveolae, Caveolin proteins, Signal transduction, Oncogenes, Cell transformation, Tumor suppression BACKGROUND AND OVERVIEW tissues suggests other regulatory functions for this gene fam- ily (Fig. 1). Caveolin has been re-named caveolin-1 [9, 10]. As far as organelles are concerned, caveolae are a work in Because the responsibilities assigned to caveolins and ca- progress. Since their discovery more than 40 years ago [1, 2] veolae continue to increase, this review will focus on two these 50- to 100-nm vesicles (Fig. 1) have been assigned main areas of caveolae-related research: (1) caveolin struc- several important functions. These jobs include potocytosis, ture and function and (2) caveolae-associated signal trans- transcytosis (in endothelial cells) and signal transduction duction. The latter discussion will highlight the involve- [3, 4]. The molecular details associated with each of these ment of caveolins/caveolae in the Ras-MAP kinase pathway tasks are being teased from the cells that bear caveolae— and in phosphatidylinositol (PI) metabolism, as well as their namely, endothelial cells; adipocytes; cardiac, smooth and interactions with G proteins, epidermal growth factor receptor striated myocytes; epithelial cells; and type I pneumocytes. (EGF receptor), platelet-derived growth factor receptor Although their original definition was morphological, ca- (PDGF receptor) and endothelial nitric oxide synthase veolae are now defined as cell-membrane invaginations (eNOS). Recent studies linking caveolae to human disease that contain the marker protein caveolin (a.k.a., VIP21) [cancer, muscular dystrophy (MD), Alzheimer’s disease, [5–7] and are enriched in glycosylphosphatidylinositol- transmissible spongiform encephalopathy (TSE, scrapie)] anchored proteins, cholesterol and glycosphingolipids. This also will be considered. specialised lipid composition has allowed investigators to purify caveolae by using detergents, inasmuch as caveolae CAVEOLIN STRUCTURE behave as Triton-insoluble complexes. Caveolin was dis- The Caveolin Gene Family covered as a phos-phorylation target of the kinase encoded Caveolin (unless specified, “caveolin” refers to caveolin-1) by the Rous sarcoma virus; that is, v-Src [8]. The implica- was identified as a principal protein component of caveolae tions for signal transduction are obvious in hindsight. The [6]. Caveolins are a family of 22,000 M r integral mem- discovery of two other caveolins, caveolin-2 [9] and caveo- brane proteins that assume an unusual hairpin-like structure lin-3 [10–13], and their differential expression in various within the membrane, with both N and C termini facing the cytoplasm (Fig. 2). Human caveolin-1 is 38% identical *Author to whom all correspondence should be addressed. E-mail: lisanti@ with and 58% similar to human caveolin-2 [9]. Caveolin-3 aecom.yu.edu Received 6 November 1997; and accepted 15 December 1997. is 65% identical with and 85% similar to caveolin-1 [10].