Role of caveolin and caveolae in insulin signaling and diabetes.

Caveolae are specialized membrane microdomains present within the plasma membrane of the vast majority of cell types. They have a unique composition in that they are highly enriched in cholesterol, sphingolipids, and their coat proteins the caveolins (-1, -2, and -3). In recent years it has been recognized that caveolae act as signaling platforms, serving as a concentrating point for numerous signaling molecules, as well as regulating flux through many distinct signaling cascades. Although caveolae are found in a variety of cell types, they are most abundant in adipose tissue. This fact has led to the intense study of the function of these organelles in adipocytes. It has now become apparent that effective insulin signaling in the adipocyte may be strictly dependent on localization of at least two insulin-responsive elements to caveolae (insulin receptor and GLUT4), as well as on a direct functional interaction between caveolin-1 and the insulin receptor. We present a critical discussion of these recent findings.

[1]  H. Lodish,et al.  Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Glenney.  Tyrosine phosphorylation of a 22-kDa protein is correlated with transformation by Rous sarcoma virus. , 1989, The Journal of biological chemistry.

[3]  M. Lisanti,et al.  Interaction of a Receptor Tyrosine Kinase, EGF-R, with Caveolins , 1997, The Journal of Biological Chemistry.

[4]  A. Saltiel,et al.  Insulin-stimulated Tyrosine Phosphorylation of Caveolin Is Specific for the Differentiated Adipocyte Phenotype in 3T3-L1 Cells* , 1997, The Journal of Biological Chemistry.

[5]  A. Saltiel,et al.  Insulin signaling pathways in time and space. , 2002, Trends in cell biology.

[6]  S. Kersten.  Mechanisms of nutritional and hormonal regulation of lipogenesis , 2001, EMBO reports.

[7]  D. Gingras,et al.  Regulation of vascular endothelial growth factor receptor-2 activity by caveolin-1 and plasma membrane cholesterol. , 2003, Molecular biology of the cell.

[8]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[9]  P. Strålfors,et al.  Localization of the insulin receptor in caveolae of adipocyte plasma membrane , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  R. Watson,et al.  The Adipocyte Plasma Membrane Caveolin Functional/Structural Organization Is Necessary for the Efficient Endocytosis of GLUT4* , 2003, The Journal of Biological Chemistry.

[11]  E. Yamada.  THE FINE STRUCTURE OF THE GALL BLADDER EPITHELIUM OF THE MOUSE , 1955, The Journal of biophysical and biochemical cytology.

[12]  A. Kimmel,et al.  Functional Studies on Native and Mutated Forms of Perilipins , 2003, The Journal of Biological Chemistry.

[13]  H. Lodish,et al.  Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles , 1994, The Journal of cell biology.

[14]  Malhotra Sk,et al.  The plasma membrane , 1988 .

[15]  G. Christ,et al.  Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. , 2001, The Journal of biological chemistry.

[16]  P. Grabham,et al.  Caveolae-associated proteins in cardiomyocytes: caveolin-2 expression and interactions with caveolin-3. , 2003, American journal of physiology. Heart and circulatory physiology.

[17]  M. Lisanti,et al.  A Role for the Caveolin Scaffolding Domain in Mediating the Membrane Attachment of Caveolin-1 , 1999, The Journal of Biological Chemistry.

[18]  A. Saltiel,et al.  The Insulin Receptor Catalyzes the Tyrosine Phosphorylation of Caveolin-1* , 2002, The Journal of Biological Chemistry.

[19]  H. Lodish,et al.  Molecular Cloning of Caveolin-3, a Novel Member of the Caveolin Gene Family Expressed Predominantly in Muscle (*) , 1996, The Journal of Biological Chemistry.

[20]  A. Kimmel,et al.  On the Control of Lipolysis in Adipocytes , 1999, Annals of the New York Academy of Sciences.

[21]  L. Jarett,et al.  Insulin and α2‐macroglobulin‐methylamine undergo endocytosis by different mechanisms in rat adipocytes: I. Comparison of cell surface events , 1987, Journal of cellular physiology.

[22]  P. Strålfors,et al.  Insulin-Stimulated Glucose Uptake Involves the Transition of Glucose Transporters to a Caveolae-Rich Fraction within the Plasma Membrane: Implications for Type II Diabetes , 1996, Molecular medicine.

[23]  J. Engelman,et al.  Palmitoylation of Caveolin-1 at a Single Site (Cys-156) Controls Its Coupling to the c-Src Tyrosine Kinase , 2001, The Journal of Biological Chemistry.

[24]  P. Strålfors,et al.  Cholesterol Depletion Disrupts Caveolae and Insulin Receptor Signaling for Metabolic Control via Insulin Receptor Substrate-1, but Not for Mitogen-activated Protein Kinase Control* , 2001, The Journal of Biological Chemistry.

[25]  J. Schaffer,et al.  Modulation of Hormone-sensitive Lipase and Protein Kinase A-mediated Lipolysis by Perilipin A in an Adenoviral Reconstituted System* , 2002, The Journal of Biological Chemistry.

[26]  K. Kandror,et al.  Expression and compartmentalization of caveolin in adipose cells: coordinate regulation with and structural segregation from GLUT4 , 1995, The Journal of cell biology.

[27]  Y. Marcel,et al.  Influence of caveolin-1 on cellular cholesterol efflux mediated by high-density lipoproteins. , 2001, American journal of physiology. Cell physiology.

[28]  David S. Park,et al.  Caveolin-1 Expression Enhances Endothelial Capillary Tubule Formation* , 2002, The Journal of Biological Chemistry.

[29]  M. Palacín,et al.  Lipid rafts are required for GLUT4 internalization in adipose cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Flier,et al.  A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance. , 1990, The Journal of biological chemistry.

[31]  T. Imamura,et al.  Two naturally occurring mutations in the kinase domain of insulin receptor accelerate degradation of the insulin receptor and impair the kinase activity. , 1994, The Journal of biological chemistry.

[32]  J. Engelman,et al.  Caveolin‐mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo , 1998, FEBS letters.

[33]  Khan Ah,et al.  Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways. , 2002 .

[34]  David E. James,et al.  Regulated transport of the glucose transporter GLUT4 , 2002, Nature Reviews Molecular Cell Biology.

[35]  C. Kahn,et al.  Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. , 2002, Developmental cell.

[36]  G. Gould,et al.  SNARE proteins are highly enriched in lipid rafts in PC12 cells: Implications for the spatial control of exocytosis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[37]  G. Clifford,et al.  Translocation of perilipin and hormone-sensitive lipase in response to lipolytic hormones. , 1997, Biochemical Society transactions.

[38]  M. Lisanti,et al.  Mutational Analysis of the Properties of Caveolin-1 , 1997, The Journal of Biological Chemistry.

[39]  H. Lodish,et al.  Flotillin and Epidermal Surface Antigen Define a New Family of Caveolae-associated Integral Membrane Proteins* , 1997, The Journal of Biological Chemistry.

[40]  F. Kraemer,et al.  Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation during the lactation cycle of the rat. , 2001, Metabolism: clinical and experimental.

[41]  J. Engelman,et al.  p42/44 MAP Kinase-dependent and -independent Signaling Pathways Regulate Caveolin-1 Gene Expression , 1999, The Journal of Biological Chemistry.

[42]  Lucas Pelkmans,et al.  Local Actin Polymerization and Dynamin Recruitment in SV40-Induced Internalization of Caveolae , 2002, Science.

[43]  Tsuneya Ikezu,et al.  Identification of Peptide and Protein Ligands for the Caveolin-scaffolding Domain , 1997, The Journal of Biological Chemistry.

[44]  G. Vallega,et al.  Immunopurification and Characterization of Rat Adipocyte Caveolae Suggest Their Dissociation from Insulin Signaling* , 2003, The Journal of Biological Chemistry.

[45]  M. Lisanti,et al.  Regulation of cAMP-mediated Signal Transduction via Interaction of Caveolins with the Catalytic Subunit of Protein Kinase A* , 1999, The Journal of Biological Chemistry.

[46]  G. Gould,et al.  The Vesicle- and Target-SNARE Proteins That Mediate Glut4 Vesicle Fusion Are Localized in Detergent-insoluble Lipid Rafts Present on Distinct Intracellular Membranes* , 2002, The Journal of Biological Chemistry.

[47]  P. Strålfors,et al.  Insulin induces translocation of glucose transporter GLUT4 to plasma membrane caveolae in adipocytes , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[48]  S. Wied,et al.  Redistribution of Glycolipid Raft Domain Components Induces Insulin-Mimetic Signaling in Rat Adipocytes , 2001, Molecular and Cellular Biology.

[49]  J. Engelman,et al.  Crowded little caves: structure and function of caveolae. , 1998, Cellular signalling.

[50]  M. White,et al.  IRS proteins and the common path to diabetes. , 2002, American journal of physiology. Endocrinology and metabolism.

[51]  M. Lisanti,et al.  Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. , 2003, American journal of physiology. Cell physiology.

[52]  M. Lisanti,et al.  Caveolin-deficient mice: insights into caveolar function human disease. , 2001, The Journal of clinical investigation.

[53]  M. Lisanti,et al.  A Molecular Dissection of Caveolin-1 Membrane Attachment and Oligomerization , 2000, The Journal of Biological Chemistry.

[54]  A. Saltiel,et al.  Insulin stimulates the tyrosine phosphorylation of caveolin , 1995, The Journal of cell biology.

[55]  G. Müller,et al.  Cholesterol Depletion Blocks Redistribution of Lipid Raft Components and Insulin-Mimetic Signaling by Glimepiride and Phosphoinositolglycans in Rat Adipocytes , 2002, Molecular medicine.

[56]  Makoto Kanzaki,et al.  Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10 , 2001, Nature.

[57]  D. Accili,et al.  Mouse models of insulin resistance. , 2004, American journal of physiology. Endocrinology and metabolism.

[58]  M. Connelly,et al.  Stabilization of caveolin-1 by cellular cholesterol and scavenger receptor class B type I. , 2002, Biochemistry.

[59]  M. Quon,et al.  Caveolin-1 interacts with the insulin receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells. , 1999, Molecular endocrinology.

[60]  M. Kanzaki,et al.  Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling and GLUT4 translocation , 2001, The Journal of cell biology.

[61]  A. Kimmel,et al.  Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation , 2003, The Journal of cell biology.

[62]  A. Saltiel,et al.  Activation of Glycogen Synthase by Insulin in 3T3-L1 Adipocytes Involves c-Cbl-associating Protein (CAP)-dependent and CAP-independent Signaling Pathways* , 2001, The Journal of Biological Chemistry.

[63]  C. Kahn,et al.  A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. , 1998, Molecular cell.

[64]  J. Geddes,et al.  Glutamate regulates caveolin expression in rat hippocampal neurons , 2003, Journal of neuroscience research.

[65]  T. Imamura,et al.  Hsp70 family molecular chaperones and mutant insulin receptor: differential binding specificities of BiP and Hsp70/Hsc70 determines accumulation or degradation of insulin receptor. , 1996, Biochemical and biophysical research communications.

[66]  M. Lisanti,et al.  Caveolins in cholesterol trafficking and signal transduction: implications for human disease. , 2000, Frontiers in bioscience : a journal and virtual library.

[67]  Y. Toya,et al.  Caveolin Is an Activator of Insulin Receptor Signaling* , 1998, The Journal of Biological Chemistry.

[68]  M. Kanzaki,et al.  CAP defines a second signalling pathway required for insulin-stimulated glucose transport , 2000, Nature.

[69]  D. Borchman,et al.  Isolation and lipid characterization of cholesterol-enriched fractions in cortical and nuclear human lens fibers. , 2003, Investigative ophthalmology & visual science.

[70]  David S. Park,et al.  Caveolin-1-deficient Mice Are Lean, Resistant to Diet-induced Obesity, and Show Hypertriglyceridemia with Adipocyte Abnormalities* , 2002, The Journal of Biological Chemistry.

[71]  L. Jarett,et al.  Insulin and alpha 2-macroglobulin-methylamine undergo endocytosis by different mechanisms in rat adipocytes: I. Comparison of cell surface events. , 1987, Journal of cellular physiology.

[72]  F. Kraemer,et al.  Translocation of Hormone-sensitive Lipase and Perilipin upon Lipolytic Stimulation of Rat Adipocytes* , 2000, The Journal of Biological Chemistry.

[73]  T Hayakawa,et al.  Invasion activating caveolin-1 mutation in human scirrhous breast cancers. , 2001, Cancer research.

[74]  E. V. van Donselaar,et al.  Cell-type and Tissue-specific Expression of Caveolin-2 , 1997, The Journal of Biological Chemistry.

[75]  M. Wilson,et al.  Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette. , 2000, Molecular endocrinology.

[76]  J. Flier,et al.  Functional properties of a naturally occurring Trp1200----Ser1200 mutation of the insulin receptor. , 1990, Molecular endocrinology.

[77]  M. Drab,et al.  Loss of Caveolae, Vascular Dysfunction, and Pulmonary Defects in Caveolin-1 Gene-Disrupted Mice , 2001, Science.

[78]  R. Nagaraj,et al.  Effects of deleting a tripeptide sequence observed in muscular dystrophy patients on the conformation of synthetic peptides corresponding to the scaffolding domain of caveolin-3. , 2002, Biochemical and biophysical research communications.

[79]  J. Pessin,et al.  Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways , 2002, Diabetologia.

[80]  J. Slot,et al.  Immunoelectron microscopic evidence that GLUT4 translocation explains the stimulation of glucose transport in isolated rat white adipose cells. , 2000, Journal of cell science.

[81]  P. Gargalovic,et al.  Caveolin-1 and Caveolin-2 Expression in Mouse Macrophages , 2001, The Journal of Biological Chemistry.

[82]  P. Gargalovic,et al.  Cellular apoptosis is associated with increased caveolin-1 expression in macrophages Published, JLR Papers in Press, June 1, 2003. DOI 10.1194/jlr.M300140-JLR200 , 2003, Journal of Lipid Research.

[83]  T. Imamura,et al.  Involvement of Heat Shock Protein 90 in the Degradation of Mutant Insulin Receptors by the Proteasome* , 1998, The Journal of Biological Chemistry.

[84]  A. Saltiel,et al.  Insulin stimulates tyrosine phosphorylation of the proto-oncogene product of c-Cbl in 3T3-L1 adipocytes. , 1997, The Biochemical journal.

[85]  S. Woodman,et al.  Mutational analysis identifies a short atypical membrane attachment sequence (KYWFYR) within caveolin-1. , 2002, Biochemistry.

[86]  R. Roth,et al.  Stimulation of Lipolysis and Hormone-sensitive Lipase via the Extracellular Signal-regulated Kinase Pathway* , 2001, The Journal of Biological Chemistry.

[87]  E. Krebs,et al.  Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. , 1999, Diabetes.

[88]  M. Lisanti,et al.  Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signaling Complexes” at the Plasma Membrane* , 1998, The Journal of Biological Chemistry.

[89]  T. Imamura,et al.  A mutation (Trp1193→Leu1193) in the tyrosine kinase domain of the insulin receptor associated with type A syndrome of insulin resistance , 1993, Diabetologia.