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. 1995 Nov 2;131(4):929–938. doi: 10.1083/jcb.131.4.929

Hormonal regulation of caveolae internalization

PMCID: PMC2199997  PMID: 7490294

Abstract

Caveolae undergo a cyclic transition from a flat segment of membrane to a vesicle that then returns to the cell surface. Here we present evidence that this cycle depends on a population of protein kinase C- alpha (PKC-alpha) molecules that reside in the caveolae membrane where they phosphorylate a 90-kD protein. This cycle can be interrupted by treatment of the cells with phorbol-12,13-dibutyrate or agents that raise the concentration of diacylglycerol in the cell. Each of these conditions displaces PKC-alpha from caveolae, inhibits the phosphorylation of the 90-kD protein, and prevents internalization. Caveolae also contain a protein phosphatase that dephosphorylates the 90-kD once PKC-alpha is gone. A similar dissociation of PKC-alpha from caveolae and inhibition of invagination was observed when cells were treated with histamine. This effect was blocked by pyrilamine but not cimetidine, indicating the involvement of histamine H1 receptors. These findings suggest that the caveolae internalization cycle is hormonally regulated.

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Selected References

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  1. Anderson R. G. Caveolae: where incoming and outgoing messengers meet. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10909–10913. doi: 10.1073/pnas.90.23.10909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson R. G., Kamen B. A., Rothberg K. G., Lacey S. W. Potocytosis: sequestration and transport of small molecules by caveolae. Science. 1992 Jan 24;255(5043):410–411. doi: 10.1126/science.1310359. [DOI] [PubMed] [Google Scholar]
  3. Anderson R. G. Potocytosis of small molecules and ions by caveolae. Trends Cell Biol. 1993 Mar;3(3):69–72. doi: 10.1016/0962-8924(93)90065-9. [DOI] [PubMed] [Google Scholar]
  4. Brown D. A., Rose J. K. Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell. 1992 Feb 7;68(3):533–544. doi: 10.1016/0092-8674(92)90189-j. [DOI] [PubMed] [Google Scholar]
  5. Chabre M. Aluminofluoride and beryllofluoride complexes: a new phosphate analogs in enzymology. Trends Biochem Sci. 1990 Jan;15(1):6–10. doi: 10.1016/0968-0004(90)90117-t. [DOI] [PubMed] [Google Scholar]
  6. Chang W. J., Rothberg K. G., Kamen B. A., Anderson R. G. Lowering the cholesterol content of MA104 cells inhibits receptor-mediated transport of folate. J Cell Biol. 1992 Jul;118(1):63–69. doi: 10.1083/jcb.118.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chang W. J., Ying Y. S., Rothberg K. G., Hooper N. M., Turner A. J., Gambliel H. A., De Gunzburg J., Mumby S. M., Gilman A. G., Anderson R. G. Purification and characterization of smooth muscle cell caveolae. J Cell Biol. 1994 Jul;126(1):127–138. doi: 10.1083/jcb.126.1.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chun M., Liyanage U. K., Lisanti M. P., Lodish H. F. Signal transduction of a G protein-coupled receptor in caveolae: colocalization of endothelin and its receptor with caveolin. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11728–11732. doi: 10.1073/pnas.91.24.11728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Daum P. R., Downes C. P., Young J. M. Histamine stimulation of inositol 1-phosphate accumulation in lithium-treated slices from regions of guinea pig brain. J Neurochem. 1984 Jul;43(1):25–32. doi: 10.1111/j.1471-4159.1984.tb06674.x. [DOI] [PubMed] [Google Scholar]
  10. Dupree P., Parton R. G., Raposo G., Kurzchalia T. V., Simons K. Caveolae and sorting in the trans-Golgi network of epithelial cells. EMBO J. 1993 Apr;12(4):1597–1605. doi: 10.1002/j.1460-2075.1993.tb05804.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fra A. M., Williamson E., Simons K., Parton R. G. Detergent-insoluble glycolipid microdomains in lymphocytes in the absence of caveolae. J Biol Chem. 1994 Dec 9;269(49):30745–30748. [PubMed] [Google Scholar]
  12. Fujimoto T. Calcium pump of the plasma membrane is localized in caveolae. J Cell Biol. 1993 Mar;120(5):1147–1157. doi: 10.1083/jcb.120.5.1147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fujimoto T., Nakade S., Miyawaki A., Mikoshiba K., Ogawa K. Localization of inositol 1,4,5-trisphosphate receptor-like protein in plasmalemmal caveolae. J Cell Biol. 1992 Dec;119(6):1507–1513. doi: 10.1083/jcb.119.6.1507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Goldberg R. I., Smith R. M., Jarett L. Insulin and alpha 2-macroglobulin-methylamine undergo endocytosis by different mechanisms in rat adipocytes: I. Comparison of cell surface events. J Cell Physiol. 1987 Nov;133(2):203–212. doi: 10.1002/jcp.1041330202. [DOI] [PubMed] [Google Scholar]
  15. Hug H., Sarre T. F. Protein kinase C isoenzymes: divergence in signal transduction? Biochem J. 1993 Apr 15;291(Pt 2):329–343. doi: 10.1042/bj2910329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jemmerson R., Klier F. G., Fishman W. H. Clustered distribution of human placental alkaline phosphatase on the surface of both placental and cancer cells. Electron microscopic observations using gold-labeled antibodies. J Histochem Cytochem. 1985 Dec;33(12):1227–1234. doi: 10.1177/33.12.4067276. [DOI] [PubMed] [Google Scholar]
  17. Kamen B. A., Capdevila A. Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5983–5987. doi: 10.1073/pnas.83.16.5983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kamen B. A., Johnson C. A., Wang M. T., Anderson R. G. Regulation of the cytoplasmic accumulation of 5-methyltetrahydrofolate in MA104 cells is independent of folate receptor regulation. J Clin Invest. 1989 Nov;84(5):1379–1386. doi: 10.1172/JCI114310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kamen B. A., Smith A. K., Anderson R. G. The folate receptor works in tandem with a probenecid-sensitive carrier in MA104 cells in vitro. J Clin Invest. 1991 Apr;87(4):1442–1449. doi: 10.1172/JCI115150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kamen B. A., Wang M. T., Streckfuss A. J., Peryea X., Anderson R. G. Delivery of folates to the cytoplasm of MA104 cells is mediated by a surface membrane receptor that recycles. J Biol Chem. 1988 Sep 25;263(27):13602–13609. [PubMed] [Google Scholar]
  21. Kemp B. E., Pearson R. B., House C. M. Pseudosubstrate-based peptide inhibitors. Methods Enzymol. 1991;201:287–304. doi: 10.1016/0076-6879(91)01026-x. [DOI] [PubMed] [Google Scholar]
  22. Lisanti M. P., Scherer P. E., Vidugiriene J., Tang Z., Hermanowski-Vosatka A., Tu Y. H., Cook R. F., Sargiacomo M. Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease. J Cell Biol. 1994 Jul;126(1):111–126. doi: 10.1083/jcb.126.1.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mochly-Rosen D., Khaner H., Lopez J. Identification of intracellular receptor proteins for activated protein kinase C. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3997–4000. doi: 10.1073/pnas.88.9.3997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. PALADE G. E. Blood capillaries of the heart and other organs. Circulation. 1961 Aug;24:368–388. doi: 10.1161/01.cir.24.2.368. [DOI] [PubMed] [Google Scholar]
  25. Parton R. G., Joggerst B., Simons K. Regulated internalization of caveolae. J Cell Biol. 1994 Dec;127(5):1199–1215. doi: 10.1083/jcb.127.5.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Parton R. G. Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J Histochem Cytochem. 1994 Feb;42(2):155–166. doi: 10.1177/42.2.8288861. [DOI] [PubMed] [Google Scholar]
  27. Raposo G., Dunia I., Delavier-Klutchko C., Kaveri S., Strosberg A. D., Benedetti E. L. Internalization of beta-adrenergic receptor in A431 cells involves non-coated vesicles. Eur J Cell Biol. 1989 Dec;50(2):340–352. [PubMed] [Google Scholar]
  28. Ritter T. E., Fajardo O., Matsue H., Anderson R. G., Lacey S. W. Folate receptors targeted to clathrin-coated pits cannot regulate vitamin uptake. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3824–3828. doi: 10.1073/pnas.92.9.3824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Roettger B. F., Rentsch R. U., Pinon D., Holicky E., Hadac E., Larkin J. M., Miller L. J. Dual pathways of internalization of the cholecystokinin receptor. J Cell Biol. 1995 Mar;128(6):1029–1041. doi: 10.1083/jcb.128.6.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ron D., Chen C. H., Caldwell J., Jamieson L., Orr E., Mochly-Rosen D. Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):839–843. doi: 10.1073/pnas.91.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rothberg K. G., Heuser J. E., Donzell W. C., Ying Y. S., Glenney J. R., Anderson R. G. Caveolin, a protein component of caveolae membrane coats. Cell. 1992 Feb 21;68(4):673–682. doi: 10.1016/0092-8674(92)90143-z. [DOI] [PubMed] [Google Scholar]
  32. Rothberg K. G., Ying Y. S., Kolhouse J. F., Kamen B. A., Anderson R. G. The glycophospholipid-linked folate receptor internalizes folate without entering the clathrin-coated pit endocytic pathway. J Cell Biol. 1990 Mar;110(3):637–649. doi: 10.1083/jcb.110.3.637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sanan D. A., Anderson R. G. Simultaneous visualization of LDL receptor distribution and clathrin lattices on membranes torn from the upper surface of cultured cells. J Histochem Cytochem. 1991 Aug;39(8):1017–1024. doi: 10.1177/39.8.1906908. [DOI] [PubMed] [Google Scholar]
  34. Shenoy-Scaria A. M., Dietzen D. J., Kwong J., Link D. C., Lublin D. M. Cysteine3 of Src family protein tyrosine kinase determines palmitoylation and localization in caveolae. J Cell Biol. 1994 Jul;126(2):353–363. doi: 10.1083/jcb.126.2.353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Simionescu N., Lupu F., Simionescu M. Rings of membrane sterols surround the openings of vesicles and fenestrae, in capillary endothelium. J Cell Biol. 1983 Nov;97(5 Pt 1):1592–1600. doi: 10.1083/jcb.97.5.1592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Smart E. J., Foster D. C., Ying Y. S., Kamen B. A., Anderson R. G. Protein kinase C activators inhibit receptor-mediated potocytosis by preventing internalization of caveolae. J Cell Biol. 1994 Feb;124(3):307–313. doi: 10.1083/jcb.124.3.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Smart E. J., Ying Y. S., Conrad P. A., Anderson R. G. Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation. J Cell Biol. 1994 Dec;127(5):1185–1197. doi: 10.1083/jcb.127.5.1185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stahl A., Mueller B. M. The urokinase-type plasminogen activator receptor, a GPI-linked protein, is localized in caveolae. J Cell Biol. 1995 Apr;129(2):335–344. doi: 10.1083/jcb.129.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tilly B. C., Tertoolen L. G., Lambrechts A. C., Remorie R., de Laat S. W., Moolenaar W. H. Histamine-H1-receptor-mediated phosphoinositide hydrolysis, Ca2+ signalling and membrane-potential oscillations in human HeLa carcinoma cells. Biochem J. 1990 Feb 15;266(1):235–243. doi: 10.1042/bj2660235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Tran D., Carpentier J. L., Sawano F., Gorden P., Orci L. Ligands internalized through coated or noncoated invaginations follow a common intracellular pathway. Proc Natl Acad Sci U S A. 1987 Nov;84(22):7957–7961. doi: 10.1073/pnas.84.22.7957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. YAMADA E. The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol. 1955 Sep 25;1(5):445–458. doi: 10.1083/jcb.1.5.445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ying Y. S., Anderson R. G., Rothberg K. G. Each caveola contains multiple glycosyl-phosphatidylinositol-anchored membrane proteins. Cold Spring Harb Symp Quant Biol. 1992;57:593–604. doi: 10.1101/sqb.1992.057.01.065. [DOI] [PubMed] [Google Scholar]

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