Multiple Functions of Caveolin-1

endoplasmic reticulum platelet-derived growth factor platelet-derived growth factor receptor autocrine motility factor transforming growth factor tyrosine kinase A/nerve growth factor receptor p75 neurotrophin receptor epidermal growth factor epidermal growth factor receptor glutathione S-transferase endothelial nitric-oxide synthase neuronal nitric-oxide synthase phospholipase C inositol triphosphate receptor Rous sarcoma virus transforming gene Src family tyrosine kinase C-terminal Src kinase G-protein-coupled receptor kinase 1 phospholipase D protein kinase C protein kinase A Src family tyrosine kinase urokinase-type plasminogen activator receptor heat shock protein 56 growth factor receptor bound protein S, G2 phase nuclear antigen GM1 ganglioside GD3 ganglioside immunoprecipitation phosphotyrosine high density lipoprotein The amino acid sequence of caveolin-1 predicts that it is an integral membrane protein, and there is strong experimental evidence that it has this property. For example, caveolin-1 is co-translationally inserted into the ER1 and shipped to the Golgi apparatus where it is incorporated into lipid domains that sort molecules for shipment to the cell surface (1Smart E.J. Graf G.A. McNiven M.A. Sessa W.C. Engelman J.A. Scherer P.E. Okamoto T. Lisanti M.P. Mol. Cell. Biol. 1999; 19: 7289-7304Crossref PubMed Scopus (929) Google Scholar). The preferred location for caveolin-1 at the cell surface is the caveola, and it cannot be removed from these membranes without detergent (2Rothberg K.G. Heuser J.E. Donzell W.C. Ying Y.S. Glenney J.R. Anderson R.G. Cell. 1992; 68: 673-682Abstract Full Text PDF PubMed Scopus (1944) Google Scholar). Finally, the movements of green fluorescent protein-tagged caveolin-1 suggest that normally caveolin-1 moves with caveolae-derived vesicles to multiple interior compartments and then recycles back to the cell surface (3Thomsen P. Roepstorff K. Stahlhut M. van Deurs B. Mol. Biol. Cell. 2002; 13: 238-250Crossref PubMed Scopus (378) Google Scholar). By contrast, there is compelling evidence that caveolin-1 can be a soluble protein. Immunogold labeling first detected soluble caveolin-1 in the lumen of the ER after cells were exposed to cholesterol oxidase (4Smart E.J. Ying Y.S. Conrad P.A. Anderson R.G. J. Cell Biol. 1994; 127: 1185-1197Crossref PubMed Scopus (384) Google Scholar). Then a small pool of soluble caveolin-1 was found in fibroblast cytosol in a complex with chaperones (5Uittenbogaard A. Ying Y. Smart E.J. J. Biol. Chem. 1998; 273: 6525-6532Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). A routine survey of caveolin-1 distribution in different tissues identified cells that targeted caveolin-1 primarily to the cytosol (skeletal muscle cells and keratinocytes), to the lumen of secretory vesicles (serous cells of pancreas, fundic stomach, and salivary gland), and to mitochondria (airway epithelial cells and hepatocytes) (6Li W.P. Liu P. Pilcher B.K. Anderson R.G. J. Cell Sci. 2001; 114: 1397-1408Crossref PubMed Google Scholar, 7Liu P., Li, W.P. Machleidt T. Anderson R.G. Nat. Cell Biol. 1999; 1: 369-375Crossref PubMed Scopus (103) Google Scholar). Both the secreted and the cytosolic caveolin-1 appear to be embedded in lipoprotein-like particles, which may explain why they are soluble. Thus, caveolin-1 is an unusual protein that can be both an integral membrane protein and soluble in multiple cellular compartments. We believe this property is an important clue about its function. Caveolin-1 (VIP21) was first identified as a tyrosine-phosphorylated protein in Rous sarcoma transformed cells (8Glenney J.R. J. Biol. Chem. 1989; 264: 20163-20166Abstract Full Text PDF PubMed Google Scholar) that was enriched in both caveolae (2Rothberg K.G. Heuser J.E. Donzell W.C. Ying Y.S. Glenney J.R. Anderson R.G. Cell. 1992; 68: 673-682Abstract Full Text PDF PubMed Scopus (1944) Google Scholar) and vesicles targeted to the apical surface of polarized epithelial cells (9Kurzchalia T.V. Dupree P. Parton R.G. Kellner R. Virta H. Lehnert M. Simons K. J. Cell Biol. 1992; 118: 1003-1014Crossref PubMed Scopus (467) Google Scholar). Caveolae (plasmalemmal vesicles) were first identified in 1953–1955 as endocytic structures that transport molecules across endothelial cells (10Anderson R.G. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1741) Google Scholar). Typically caveolae are recognized in thin section EM images by their flask-shaped morphology. The cytosolic surface of each caveola, however, has a striated coat (2Rothberg K.G. Heuser J.E. Donzell W.C. Ying Y.S. Glenney J.R. Anderson R.G. Cell. 1992; 68: 673-682Abstract Full Text PDF PubMed Scopus (1944) Google Scholar) that is best seen in rapid-freeze deep-etch images. Caveolin-1 has been localized to the filaments that make up this coat. Caveolin-1 readily oligomerizes in vitro(1Smart E.J. Graf G.A. McNiven M.A. Sessa W.C. Engelman J.A. Scherer P.E. Okamoto T. Lisanti M.P. Mol. Cell. Biol. 1999; 19: 7289-7304Crossref PubMed Scopus (929) Google Scholar), and recent structural studies indicate the N-terminal 101 amino acids assemble into heptameric subunits that appear to be the basic building block of each filament (11Fernandez I. Ying Y.-S. Albanesi J. Anderson R.G.W. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11193-11198Crossref PubMed Scopus (124) Google Scholar). The characteristics of other membrane coats, such as clathrin, COPI, and COPII, led to the expectation that caveolin was necessary for caveolae budding. Indeed, rapid-freeze deep-etch images showed caveolin-1 coats decorating membranes in different stages of membrane invagination, and cells lacking caveolin-1 appear not to have flask-shaped membranes (12Anderson R.G. Jacobson K. Science. 2002; 296: 1821-1825Crossref PubMed Scopus (1026) Google Scholar). Recent studies, however, call in to question whether caveolin-1 is needed for internalization and traffic of caveolae (see below). There are three caveolin genes expressed in mammals (designated caveolin-1, -2, and -3), and they code for five different isoforms of the protein (1Smart E.J. Graf G.A. McNiven M.A. Sessa W.C. Engelman J.A. Scherer P.E. Okamoto T. Lisanti M.P. Mol. Cell. Biol. 1999; 19: 7289-7304Crossref PubMed Scopus (929) Google Scholar). Most tissues in the body express at least one of these isoforms. Notably lacking are cultured lymphocytes and certain neuronal cells. Caveolin-1 and -2 are usually co-expressed and assemble into hetero-oligomers in the ER and Golgi apparatus (13Scheiffele P. Verkade Fra M. Virta Simons Ikonen J. Cell Biol. 1998; 140: 795-806Crossref PubMed Scopus (265) Google Scholar). These oligomers mature into higher molecular weight complexes once they reach caveolae. Interestingly, caveolin-2 appears unable to exit the Golgi apparatus by itself (14Parolini I. Sargiacomo M. Galbiati F. Rizzo G. Grignani F. Engelman J.A. Okamoto T. Ikezu T. Scherer P.E. Mora R. Rodriguez-Boulan E. Peschle C. Lisanti M.P. J. Biol. Chem. 1999; 274: 25718-25725Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar) and is rapidly degraded in cells not expressing caveolin-1. In skeletal and heart muscle cells, caveolin-3 replaces caveolin-1 in caveolae. Skeletal muscle cells selectively express the β isoform of caveolin-1, but it is targeted to the cytosol where it tends to collect along the Z-line (6Li W.P. Liu P. Pilcher B.K. Anderson R.G. J. Cell Sci. 2001; 114: 1397-1408Crossref PubMed Google Scholar). One way to understand the function of a protein is to identify its interacting partners. A variety of proteins have been identified that interact with either caveolin-1 or tyrosine-phosphorylated caveolin-1 (pY14). In addition, caveolin-1 interacts with both lipids and lipid anchors on proteins (Table I). These interactions predict that caveolin-1 functions in lipid traffic, membrane traffic, and signal transduction.Table IA partial list of proteins and lipids that interact with caveolin-1ProteinsInteracting region of Cav-1Detection methodRef.PDGFRα and -β82–101IP48Yamamoto M. Toya Y. Jensen R.A. Ishikawa Y. Exp. Cell Res. 1999; 247: 380-388Crossref PubMed Scopus (102) Google ScholarEGFR61–101IP49Couet J. Sargiacomo M. Lisanti M.P. J. Biol. Chem. 1997; 272: 30429-30438Abstract Full Text Full Text PDF PubMed Scopus (555) Google ScholarInsulin receptor81–101IP50Yamamoto M. Toya Y. Schwencke C. Lisanti M.P. Myers Jr., M.G. Ishikawa Y. J. Biol. Chem. 1998; 273: 26962-26968Abstract Full Text Full Text PDF PubMed Scopus (254) Google ScholarTGFβRI61–101IP51Razani B. Zhang X.L. Bitzer M. von Gersdorff G. Bottinger E.P. Lisanti M.P. J. Biol. Chem. 2001; 276: 6727-6738Abstract Full Text Full Text PDF PubMed Scopus (293) Google ScholarTrkA/p75NTRWhole proteinIP52Bilderback T.R. Grigsby R.J. Dobrowsky R.T. J. Biol. Chem. 1997; 272: 10922-10927Abstract Full Text Full Text PDF PubMed Scopus (160) Google ScholarHedgehog receptor81–101IP53Karpen H.E. Bukowski J.T. Hughes T. Gratton J.P. Sessa W.C. Gailani M.R. J. Biol. Chem. 2001; 276: 19503-19511Abstract Full Text Full Text PDF PubMed Scopus (106) Google ScholarEstrogen receptor82–101IP54Schlegel A. Wang C. Pestell R.G. Lisanti M.P. Biochem. J. 2001; 359: 203-210Crossref PubMed Scopus (66) Google ScholarAndrogen receptorWhole proteinIP/two hybrid55Lu M.L. Schneider M.C. Zheng Y. Zhang X. Richie J.P. J. Biol. Chem. 2001; 276: 13442-13451Abstract Full Text Full Text PDF PubMed Scopus (212) Google ScholarH-Ras61–101GST56Song K.S., Li, S. Okamoto T. Quilliam L.A. Sargiacomo M. Lisanti M.P. J. Biol. Chem. 1996; 271: 9690-9697Abstract Full Text Full Text PDF PubMed Scopus (924) Google ScholarGαq/Gαo/GαsWhole proteinGST57Li S. Okamoto T. Chun M. Sargiacomo M. Casanova J.E. Hansen S.H. Nishimoto I. Lisanti M.P. J. Biol. Chem. 1995; 270: 15693-15701Abstract Full Text Full Text PDF PubMed Scopus (560) Google ScholarAdenylyl cyclase/PLCβ282–101IP58Schreiber S. Fleischer J. Breer H. Boekhoff I. J. Biol. Chem. 2000; 275: 24115-24123Abstract Full Text Full Text PDF PubMed Scopus (44) Google ScholarTrp1/IP3R/Gq11Whole proteinIP59Lockwich T.P. Liu X. Singh B.B. Jadlowiec J. Weiland S. Ambudkar I.S. J. Biol. Chem. 2000; 275: 11934-11942Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholarc-Src61–101IP37Li S. Couet J. Lisanti M.P. J. Biol. Chem. 1996; 271: 29182-29190Abstract Full Text Full Text PDF PubMed Scopus (682) Google ScholarLyn81–101IP60Muller G. Jung C. Wied S. Welte S. Jordan H. Frick W. Mol. Cell. Biol. 2001; 21: 4553-4567Crossref PubMed Scopus (87) Google ScholarCskPY14Two hybrid/IP61Cao H. Courchesne W.E. Mastick C.C. J. Biol. Chem. 2002; 277: 8771-8774Abstract Full Text Full Text PDF PubMed Scopus (183) Google ScholarGRK1, -2, and -561–101IP62Carman C.V. Lisanti M.P. Benovic J.L. J. Biol. Chem. 1999; 274: 8858-8864Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarCOX-2Whole proteinIP41Liou J.Y. Deng W.G. Gilroy D.W. Shyue S.K. Wu K.K. J. Biol. Chem. 2001; 276: 34975-34982Abstract Full Text Full Text PDF PubMed Scopus (87) Google ScholarPLD/PKCα82–101IP63Kim J.H. Han J.M. Lee S. Kim Y. Lee T.G. Park J.B. Lee S.D. Suh P.G. Ryu S.H. Biochemistry. 1999; 38: 3763-3769Crossref PubMed Scopus (59) Google ScholarPKA81–101IP64Razani B. Rubin C.S. Lisanti M.P. J. Biol. Chem. 1999; 274: 26353-26360Abstract Full Text Full Text PDF PubMed Scopus (155) Google ScholarPKCɛWhole proteinIP65Wu D. Foreman T.L. Gregory C.W. McJilton M.A. Wescott G.G. Ford O.H. Alvey R.F. Mohler J.L. Terrian D.M. Cancer Res. 2002; 62: 2423-2429PubMed Google ScholarIntegrin/cortactin/SrcWhole proteinIP66Wei Y. Yang X. Liu Q. Wilkins J.A. Chapman H.A. J. Cell Biol. 1999; 144: 1285-1294Crossref PubMed Scopus (372) Google ScholarIntegrin(α,β)/Shc/FynWhole proteinIP67Wary K.K. Mariotti A. Zurzolo C. Giancotti F.G. Cell. 1998; 94: 625-634Abstract Full Text Full Text PDF PubMed Scopus (622) Google ScholaruPAR/integrinβ1Whole proteinIP68Wei Y. Lukashev M. Simon D.I. Bodary S.C. Rosenberg S. Doyle M.V. Chapman H.A. Science. 1996; 273: 1551-1555Crossref PubMed Scopus (699) Google ScholareNOS82–101IP69Garcia-Cardena G. Fan R. Stern D.F. Liu J.W. Sessa W.C. J. Biol. Chem. 1996; 271: 27237-27240Abstract Full Text Full Text PDF PubMed Scopus (432) Google ScholarnNOSWhole proteinGST70Venema V.J., Ju, H. Zou R. Venema R.C. J. Biol. Chem. 1997; 272: 28187-28190Abstract Full Text Full Text PDF PubMed Scopus (221) Google ScholarFlotillin 1, 2/Cav-2Whole proteinIP71Volonte D. Galbiati F., Li, S. Nishiyama K. Okamoto T. Lisanti M.P. J. Biol. Chem. 1999; 274: 12702-12709Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar190-kDa pYWhole proteinIP72Liu P. Ying Y., Ko, Y.G. Anderson R.G. J. Biol. Chem. 1996; 271: 10299-10303Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar30-kDa pYWhole proteinIP73Mastick C.C. Saltiel A.R. J. Biol. Chem. 1997; 272: 20706-20714Abstract Full Text Full Text PDF PubMed Scopus (131) Google ScholarHSP56/cyc40/cycAWhole proteinIP5Uittenbogaard A. Ying Y. Smart E.J. J. Biol. Chem. 1998; 273: 6525-6532Abstract Full Text Full Text PDF PubMed Scopus (272) Google ScholarFilamin1–101GST/2 hybrid74Stahlhut M. van Deurs B. Mol. Biol. Cell. 2000; 11: 325-337Crossref PubMed Scopus (268) Google ScholarGrb7PY 14GST75Lee H. Woodman S.E. Engelman J.A. Volonte D. Galbiati F. Kaufman H.L. Lublin D.M. Lisanti M.P. J. Biol. Chem. 2001; 276: 35150-35158Abstract Full Text Full Text PDF PubMed Scopus (105) Google ScholarStriatin/SG2NA/zinedinWhole proteinIP/GST76Gaillard S. Bartoli M. Castets F. Monneron A. FEBS Lett. 2001; 508: 49-52Crossref PubMed Scopus (58) Google ScholarConnexin 4382–101 and 135–178IP77Schubert A.L. Schubert W. Spray D.C. Lisanti M.P. Biochemistry. 2002; 41: 5754-5764Crossref PubMed Scopus (233) Google ScholarLipidsInteracting region of Cav-1Detection methodRef.CholesterolWhole proteinOverlay16Murata M. Peranen J. Schreiner R. Wieland F. Kurzchalia T.V. Simons K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10339-10343Crossref PubMed Scopus (781) Google ScholarFatty acidsWhole proteinIP17Trigatti B.L. Anderson R.G. Gerber G.E. Biochem. Biophys. Res. Commun. 1999; 255: 34-39Crossref PubMed Scopus (187) Google ScholarGM1Whole proteinIP18Fra A.M. Masserini M. Palestini P. Sonnino S. Simons K. FEBS Lett. 1995; 375: PubMed Scopus Google K. Y. T. Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus (183) Google in a is for the (2Rothberg K.G. Heuser J.E. Donzell W.C. Ying Y.S. Glenney J.R. Anderson R.G. Cell. 1992; 68: 673-682Abstract Full Text PDF PubMed Scopus (1944) Google Scholar) and function of caveolae K.G. Anderson R.G. J. Cell Biol. 1992; 118: PubMed Scopus (221) Google Scholar). In have that caveolin-1 interacts with cholesterol M. Peranen J. Schreiner R. Wieland F. Kurzchalia T.V. Simons K. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10339-10343Crossref PubMed Scopus (781) Google Scholar), that it may membrane cholesterol in caveolae. Caveolin-1 with high acids B.L. Anderson R.G. Gerber G.E. Biochem. Biophys. Res. Commun. 1999; 255: 34-39Crossref PubMed Scopus (187) Google Scholar), which may for its to interact with the GM1 A.M. Masserini M. Palestini P. Sonnino S. Simons K. FEBS Lett. 1995; 375: PubMed Scopus Google Scholar) that collect in caveolae. A strong can be however, that caveolin-1 a in the and of cellular cholesterol by caveolae. The first caveolae were in cholesterol traffic from the that in cholesterol moves to surface caveolae after in the ER E.J. Ying Y. Donzell W.C. Anderson R.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). caveolae the cholesterol then moves rapidly to other of the membrane and to the The transport of cholesterol to the cell surface is on the of caveolin-1 E.J. Ying Y. Donzell W.C. Anderson R.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). caveolin-1 is in the transport of cholesterol in these cells A. Smart E.J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). ER to membrane transport of cholesterol is by and this caveolin-1 to in membranes (1Smart E.J. Graf G.A. McNiven M.A. Sessa W.C. Engelman J.A. Scherer P.E. Okamoto T. Lisanti M.P. Mol. Cell. Biol. 1999; 19: 7289-7304Crossref PubMed Scopus (929) Google Scholar). Finally, of a caveolin-3 the cholesterol of caveolae in cells, which can be by the of cholesterol S. R. A. A. M. E. B. Parton R.G. Nat. Cell Biol. 1999; 1: PubMed Scopus Google Scholar). The of of is not it is that it with caveolin-1 function. membrane cholesterol can to the ER Y. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). cholesterol and cholesterol in bound to can to from caveolae G.A. Smart E.J. 1999; PubMed Scopus Google Scholar). of caveolin has been to cholesterol P.E. J. Res. 1997; 38: Full Text PDF PubMed Google Scholar), but the of caveolin to the ER after the of caveolae cholesterol (4Smart E.J. Ying Y.S. Conrad P.A. Anderson R.G. J. Cell Biol. 1994; 127: 1185-1197Crossref PubMed Scopus (384) Google Scholar) it has a in cholesterol The is can caveolin-1, which is an integral membrane protein in cholesterol to compartments the A to this may be cytosolic caveolin-1. have the (5Uittenbogaard A. Ying Y. Smart E.J. J. Biol. Chem. 1998; 273: 6525-6532Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar) that the cytosol of cells a pool of soluble caveolin-1. caveolin-1 is with cholesterol and a protein that is embedded in a with the J. Y. K. R. S. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) and density (6Li W.P. Liu P. Pilcher B.K. Anderson R.G. J. Cell Sci. 2001; 114: 1397-1408Crossref PubMed Google Scholar) of that cells caveolae appear to with cytosolic caveolin-1. the may cholesterol from the ER to the membrane G.A. Smart E.J. 1999; PubMed Scopus Google Scholar). it has been found that to the of cytosolic lipid caveolin-1, and J. Y. K. R. S. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). caveolin-1 is secreted by secretory cells in the that lipid in the are in the of secreted caveolin may be important for the of lipid A. R. M. S. Ikonen E. Parton R.G. J. Cell Biol. 2001; PubMed Scopus Google Scholar). In caveolin-1 has a function in and lipid function may for the high of caveolin-1 in (6Li W.P. Liu P. Pilcher B.K. Anderson R.G. J. Cell Sci. 2001; 114: 1397-1408Crossref PubMed Google Scholar) as as the in lipid that are seen in caveolin-1 B. T.P. Wang P.G. Park Li, M. B. L.A. Scherer P.E. Lisanti M.P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Caveolin-1 is not a lipid protein to be of a lipid that lipids to the way that lipids The lipid and protein of this to be The where one caveolin-1 to function in membrane traffic is at the Caveolae are for their endocytic in R.G. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1741) Google Scholar). Caveolin-1 proteins to caveolae the way that to function as a molecular that membrane and budding. There is however, that caveolin-1 functions this Caveolin-1 has been to interact with receptor tyrosine (see the receptor The for to however, is in the of the receptor M. Anderson R.G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar), an with caveolin-1 has to with to caveolae. A recent the that caveolin-1 is for caveolae of autocrine motility factor normally by both and caveolae G. Y. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The caveolae the factor to the ER it to to the however, appears to in cells in caveolin-1. These cells flask-shaped which is in with but of to the ER is in cells expressing caveolin-1. of caveolae as the of was by these cells with a which from these the cells flask-shaped membranes that were from found in cells, and they In other without caveolin-1 caveolae internalization is that flask-shaped caveolae are to in thin section images internalization is These are in with a recent that internalization of a protein the caveolae is the of whether the cells express caveolin-1 Nat. Cell Biol. 2002; PubMed Scopus Google Scholar). In to these studies, of by endothelial cells from caveolin-1 is B. Engelman J.A. Wang Schubert W. Zhang X.L. F. Li, M. Pestell D. Jr., H. B. G. W. Lisanti M.P. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). not however, whether the was of caveolae or the of the receptor at the cell the studies on are then caveolin-1 be a of caveolae membrane internalization and this A structural function for caveolin-1 with recent on the of membrane fluorescent protein (3Thomsen P. Roepstorff K. Stahlhut M. van Deurs B. Mol. Biol. Cell. 2002; 13: 238-250Crossref PubMed Scopus (378) Google Scholar). has an for the of caveolae and caveolae-derived caveolae on the surface of cells are and not to interior of the cell (3Thomsen P. Roepstorff K. Stahlhut M. van Deurs B. Mol. Biol. Cell. 2002; 13: 238-250Crossref PubMed Scopus (378) Google Scholar). Caveolae internalization is by and tyrosine (10Anderson R.G. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1741) Google Scholar). virus can this and their internalization caveolae by an tyrosine kinase J. A. Nat. Cell Biol. 2001; PubMed Scopus Google Scholar). Caveolae to collect in of the cell and they a of One is which may interact with caveolin-1 (Table I). an important function of caveolin-1 may be to the of caveolae with the whether caveolae are at the cell surface or to interior in may be by tyrosine of caveolin-1. the of caveolin-1 as a caveolae protein, were for caveolae from tissues as as cells (10Anderson R.G. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1741) Google Scholar). of these was the that caveolae are in multiple molecules that function in cellular signal (10Anderson R.G. Annu. Rev. Biochem. 1998; 67: 199-225Crossref PubMed Scopus (1741) Google Scholar). The to rapidly these membrane domains led to the that molecules are with caveolae. For example, have in caveolae but are enriched in is to caveolae at the as moves to membranes C. Smart E.J. Anderson R.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). the have been localized to and they are after caveolae are from the cell P. Ying Y. Anderson R.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus (194) Google Scholar). In of these it was to that caveolin-1 signal by molecules to caveolae and their A function for caveolin-1 of a of the of this to M.P. Scherer P. Sargiacomo M. Cell Biol. 1994; Full Text PDF PubMed Scopus Google Scholar). caveolin-1 oligomers in and to a region of the amino acids and which is on the N-terminal of the membrane region M. Scherer P.E. E. M.C. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar). to with the that caveolin-1 is a structural of the caveolae coat. S. Couet J. Lisanti M.P. J. Biol. Chem. 1996; 271: 29182-29190Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar) were the first to that a the amino acid sequence and 101 in caveolin-1 Src kinase a protein amino acids of caveolin-1 interacts with The sequence and 101 was the caveolin-1 S. Couet J. Lisanti M.P. J. Biol. Chem. 1996; 271: 29182-29190Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar). a was to from a with the and where is Li, S. Okamoto T. Ikezu T. Lisanti M.P. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). but not proteins one of these in E.J. Graf G.A. McNiven M.A. Sessa W.C. Engelman J.A. Scherer P.E. Okamoto T. Lisanti M.P. Mol. Cell. Biol. 1999; 19: 7289-7304Crossref PubMed Scopus (929) Google Scholar). A of the caveolin-1 is the that it functions to molecules T. A. Scherer P.E. Lisanti M.P. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). studies have an the caveolin-1 and molecules (see for a partial these interactions the of the as (1Smart E.J. Graf G.A. McNiven M.A. Sessa W.C. Engelman J.A. Scherer P.E. Okamoto T. Lisanti M.P. Mol. Cell. Biol. 1999; 19: 7289-7304Crossref PubMed Scopus (929) Google Scholar), in the M. Y. G. M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus (102) Google Scholar) or has at J.Y. Deng W.G. Gilroy D.W. Shyue S.K. Wu K.K. J. Biol. Chem. 2001; 276: 34975-34982Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). The in these studies the of the a on in however, this has been found to after into cells M. Gratton J.P. F. G. Sessa W.C. Nat. 2000; PubMed Scopus Google Scholar). The of studies are in basic with the caveolin-1 the other not the that caveolin-1 is a it to interacting with proteins that collect in but there is way of the of its The may be a region that to proteins in the Recent studies on the of the region of caveolin-1 suggest that amino acids of the have (11Fernandez I. Ying Y.-S. Albanesi J. Anderson R.G.W. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11193-11198Crossref PubMed Scopus (124) Google Scholar). of and amino acids one of the the other is in amino Thus, the interacting surface of the is a in addition, interactions caveolae coat filament has a to interact with membranes A. Scherer P.E. Lisanti M.P. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus (131) Google Scholar). is the of evidence that the functions as a or activator of cell of into this region of the traffic of the Golgi apparatus Li, W.P. Liu P. Anderson R.G. J. Cell Biol. 2000; PubMed Scopus Google Scholar), which it to whether this region of the has an on signal Indeed, a in this region of the caveolin-3 isoform is and not found at the cell surface C. F. C. P. P. M. E. M. A. M.A. Volonte D. Galbiati F. G. Lisanti M.P. F. Nat. 1998; PubMed Scopus Google Scholar). Finally, the of lacking caveolin-1 are not in with a for the in signal These have in and but their is with an for the in signal Caveolin-1 may signal an with lipids there is experimental and evidence that caveolin-1 is in caveolae cholesterol Caveolae in is for the of certain molecules to caveolae and for the One is the the and multiple molecules in caveolae. is for cholesterol in of but of the other is not the has of caveolae is it of a of the from the P. Wang P. P. M. Anderson R.G. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). it appears that cholesterol is for to with its In other caveolae lipids a that multiple molecules and their interactions with The of this on A function for caveolin-1, is to the caveolae lipid by cholesterol and it with Caveolin-1 appears to have functions in lipid membrane traffic, and cell The of these functions to be but be in the complex and traffic of this protein. A is in 1 for caveolin-1 from its of to compartments in the Caveolin-1 appears to be inserted co-translationally into the ER membrane with its and C-terminal in the 1, then is incorporated into vesicles 1, that to the Golgi apparatus in a that amino acids Li, W.P. Liu P. Anderson R.G. J. Cell Biol. 2000; PubMed Scopus Google Scholar). the Golgi apparatus caveolin-1 oligomerizes and M.P. Sargiacomo M. J. Cell Biol. 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Finally, soluble caveolin-1 can to mitochondria 1, is about the distribution of caveolin-1 is or about the for caveolin-1 from a membrane to a soluble protein. We for