Clathrin/AP-2-Dependent Endocytosis: A Novel Playground for the Pharmacological Toolbox?

  • C. Rodemer
  • V. Haucke
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 186)

Abstract

Endocytosis is a vital process for mammalian cells by which they communicate with their environment, internalize nutrients, hormones, or growth factors, or take up extracellular fluids and particles. The best studied among the various pathways to ingest material from the extracellular side is clathrin/AP-2-mediated endocytosis. The past several years have allowed us to gain unprecedented molecular insights into the role of the heterotetrameric AP-2 adaptor complex as a central protein-protein and protein-lipid interaction hub at the plasmalemma. During the initial stages of clathrin-coated pit formation, AP-2 interacts with phosphoinositides and cargo membrane proteins as well as with a variety of accessory proteins and clathrin to coordinate clathrin coat polymerization with membrane deformation and cargo recruitment. In addition, a growing list of alternative adaptors provides opportunity for clathrin-dependent cargo selective pathways of internalization and endosomal sorting. Many of these interactions are now understood in structural detail and are thus amenable to pharmacological interference. In this review we will summarize our present state of knowledge about AP-2 and its partners in endocytosis and delineate potential strategies for pharmacological manipulations.

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References

  1. Ahn S, Nelson CD, Garrison TR, Miller WE, Lefkowitz RJ (2003) Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference. Proc Natl Acad Sci USA 100:1740–1744PubMedCrossRefGoogle Scholar
  2. Altankov G, Grinnell F (1993) Depletion of intracellular potassium disrupts coated pits and reversibly inhibits cell polarization during fibroblast spreading. J Cell Biol 120:1449–1459PubMedCrossRefGoogle Scholar
  3. Bauer M, Pelkmans L (2006) A new paradigm for membrane-organizing and -shaping scaffolds. FEBS Lett 580:5559–5564PubMedCrossRefGoogle Scholar
  4. Beck KA, Keen JH (1991) Interaction of phosphoinositide cycle intermediates with the plasma membrane-associated clathrin assembly protein AP-2. J Biol Chem 266:4442–4447PubMedGoogle Scholar
  5. Berdnik D, Torok T, Gonzalez-Gaitan M, Knoblich JA (2002) The endocytic protein alpha-adaptin is required for numb-mediated asymmetric cell division in Drosophila. Dev Cell 3:221–231PubMedCrossRefGoogle Scholar
  6. Boehm M, Bonifacino JS (2001) Adaptins: the final recount. Mol Biol Cell 12:2907–2920PubMedGoogle Scholar
  7. Boll W, Rapoport I, Brunner C, Modis Y, Prehn S, Kirchhausen T (2002) The mu2 subunit of the clathrin adaptor AP-2 binds to FDNPVY and YppO sorting signals at distinct sites. Traffic 3: 590–600PubMedCrossRefGoogle Scholar
  8. Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395–447PubMedCrossRefGoogle Scholar
  9. Bonifacino JS, Lippincott-Schwartz J (2003) Coat proteins: shaping membrane transport. Nat Rev Mol Cell Biol 4:409–414PubMedCrossRefGoogle Scholar
  10. Chen YJ, Zhang P, Egelman EH, Hinshaw JE (2004) The stalk region of dynamin drives the constriction of dynamin tubes. Nat Struct Mol Biol 11:574–557PubMedCrossRefGoogle Scholar
  11. Collins BM, McCoy AJ, Kent HM, Evans PR, Owen DJ (2002) Molecular architecture and functional model of the endocytic AP2 complex. Cell 109:523–535PubMedCrossRefGoogle Scholar
  12. Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44PubMedCrossRefGoogle Scholar
  13. Cremona O, Di Paolo G, Wenk MR, Luthi A, Kim WT, Takei K, Daniell L, Nemoto Y, Shears SB, Flavell RA, McCormick DA, De Camilli P (1999) Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 99:179–188PubMedCrossRefGoogle Scholar
  14. Dell’Angelica EC (2001) Clathrin-binding proteins: got a motif? Join the network! Trends Cell Biol 11: 315–318PubMedCrossRefGoogle Scholar
  15. Derkach VA, Oh MC, Guire ES, Soderling TR (2007) Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci 8:101–113PubMedCrossRefGoogle Scholar
  16. Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657PubMedCrossRefGoogle Scholar
  17. Diril MK, Wienisch M, Jung N, Klingauf J, Haucke V (2006) Stonin 2 is an AP-2-dependent endocytic sorting adaptor for synaptotagmin internalization and recycling. Dev Cell 10:233–244PubMedCrossRefGoogle Scholar
  18. Dudu V, Pantazis P, Gonzalez-Gaitan M (2004) Membrane traffic during embryonic development: epithelial formation, cell fate decisions and differentiation. Curr Opin Cell Biol 16: 407–414PubMedCrossRefGoogle Scholar
  19. Edeling MA, Mishra SK, Keyel PA, Steinhauser AL, Collins BM, Roth R, Heuser JE, Owen DJ, Traub LM (2006a) Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly. Dev Cell 10:329–342PubMedCrossRefGoogle Scholar
  20. Edeling MA, Smith C, Owen D (2006b) Life of a clathrin coat: insights from clathrin and AP structures. Nat Rev Mol Cell Biol 7:32–44PubMedCrossRefGoogle Scholar
  21. Fergestad T, Broadie K (2001) Interaction of stoned and synaptotagmin in synaptic vesicle endocytosis. J Neurosci 21:1218–1227PubMedGoogle Scholar
  22. Gaidarov I, Keen JH (1999) Phosphoinositide-AP-2 interactions required for targeting to plasma membrane clathrin-coated pits. J Cell Biol 146:755–764PubMedCrossRefGoogle Scholar
  23. Gaidarov I, Smith ME, Domin J, Keen JH (2001) The class II phosphoinositide 3-kinase C2alpha is activated by clathrin and regulates clathrin-mediated membrane trafficking. Mol Cell 7:443–449PubMedCrossRefGoogle Scholar
  24. Galli T, Haucke V (2004) Cycling of synaptic vesicles: how far? How fast! Sci STKE 2004: re19CrossRefGoogle Scholar
  25. Glebov OO, Bright NA, Nichols BJ (2006) Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. Nat Cell Biol 8:46–54PubMedCrossRefGoogle Scholar
  26. Gonzalez-Gaitan M, Jackle H (1997) Role of Drosophila alpha-adaptin in presynaptic vesicle recycling. Cell 88:767–776PubMedCrossRefGoogle Scholar
  27. Gupta-Rossi N, Six E, LeBail O, Logeat F, Chastagner P, Olry A, Israel A, Brou C (2004) Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J Cell Biol 166:73–83PubMedCrossRefGoogle Scholar
  28. Hansen SH, Sandvig K, van Deurs B (1993) Clathrin and HA2 adaptors: effects of potassium depletion, hypertonic medium, and cytosol acidification. J Cell Biol 121:61–72PubMedCrossRefGoogle Scholar
  29. Harris TW, Hartwieg E, Horvitz HR, Jorgensen EM (2000) Mutations in synaptojanin disrupt synaptic vesicle recycling. J Cell Biol 150:589–600PubMedCrossRefGoogle Scholar
  30. Haucke V (2005) Phosphoinositide regulation of clathrin-mediated endocytosis. Biochem Soc Trans 33:1285–1289PubMedCrossRefGoogle Scholar
  31. Haucke V (2006) Cargo takes control of endocytosis. Cell 127:35–37PubMedCrossRefGoogle Scholar
  32. Henley JR, Krueger EW, Oswald BJ, McNiven MA (1998) Dynamin-mediated internalization of caveolae. J Cell Biol 141:85–99PubMedCrossRefGoogle Scholar
  33. Heuser J (1989) Effects of cytoplasmic acidification on clathrin lattice morphology. J Cell Biol 108:401–411PubMedCrossRefGoogle Scholar
  34. Heuser JE, Anderson RG (1989) Hypertonic media inhibit receptor-mediated endocytosis by blocking clathrin-coated pit formation. J Cell Biol 108:389–400PubMedCrossRefGoogle Scholar
  35. Heuser JE, Keen J (1988) Deep-etch visualization of proteins involved in clathrin assembly. J Cell Biol 107:877–886PubMedCrossRefGoogle Scholar
  36. Hinrichsen L, Harborth J, Andrees L, Weber K, Ungewickell EJ (2003) Effect of clathrin heavy chain- and alpha-adaptin-specific small inhibitory RNAs on endocytic accessory proteins and receptor trafficking in HeLa cells. J Biol Chem 278:45160–45170PubMedCrossRefGoogle Scholar
  37. Hinrichsen L, Meyerholz A, Groos S, Ungewickell EJ (2006) Bending a membrane: how clathrin affects budding. Proc Natl Acad Sci USA 103:8715–8720PubMedCrossRefGoogle Scholar
  38. Honing S, Ricotta D, Krauss M, Spate K, Spolaore B, Motley A, Robinson M, Robinson C, Haucke V, Owen DJ (2005) Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2. Mol Cell 18:519–531PubMedCrossRefGoogle Scholar
  39. Huang F, Khvorova A, Marshall W, Sorkin A (2004) Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J Biol Chem 279:16657–16661PubMedCrossRefGoogle Scholar
  40. Jha A, Agostinelli NR, Mishra SK, Keyel PA, Hawryluk MJ, Traub LM (2004) A novel AP-2 adaptor interaction motif initially identified in the long-splice isoform of synaptojanin 1, SJ170. J Biol Chem 279:2281–2290PubMedCrossRefGoogle Scholar
  41. Jones C, Garuti R, Michaely P, Li WP, Maeda N, Cohen JC, Herz J, Hobbs HH (2007) Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia. J Clin Invest 117:165–1674PubMedCrossRefGoogle Scholar
  42. Jost M, Simpson F, Kavran JM, Lemmon MA, Schmid SL (1998) Phosphatidylinositol-4,5-bisphosphate is required for endocytic coated vesicle formation. Curr Biol 8:1399–102PubMedCrossRefGoogle Scholar
  43. Kastning K, Kukhtina V, Kittler JT, Chen G, Pechstein A, Enders S, Lee SH, Sheng M, Yan Z, Haucke V (2007) Molecular determinants for the interaction between AMPA receptors and the clathrin adaptor complex AP-2. Proc Natl Acad Sci USA 104:2991–2996PubMedCrossRefGoogle Scholar
  44. Kirchhausen T (1999) Adaptors for clathrin-mediated traffic. Annu Rev Cell Dev Biol 15: 705–732PubMedCrossRefGoogle Scholar
  45. Kirchhausen T (2000) Clathrin. Annu Rev Biochem 69:699–727PubMedCrossRefGoogle Scholar
  46. Krauss M, Haucke V (2007) Phosphoinositides: Regulators of membrane traffic and protein function. FEBS Lett 581: 2015–2011CrossRefGoogle Scholar
  47. Krauss M, Kinuta M, Wenk MR, De Camilli P, Takei K, Haucke V (2003) ARF6 stimulates clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol phosphate kinase type Igamma. J Cell Biol 162:113–124PubMedCrossRefGoogle Scholar
  48. Lakadamyali M, Rust MJ, Zhuang X (2006) Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes. Cell 124:997–1009PubMedCrossRefGoogle Scholar
  49. Larkin JM, Brown MS, Goldstein JL, Anderson RG (1983) Depletion of intracellular potassium arrests coated pit formation and receptor-mediated endocytosis in fibroblasts. Cell 33: 273–285PubMedCrossRefGoogle Scholar
  50. Lee SH, Simonetta A, Sheng M (2004) Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron 43:221–236PubMedCrossRefGoogle Scholar
  51. Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308:512–517PubMedCrossRefGoogle Scholar
  52. Lewin DA, Mellman I (1998) Sorting out adaptors. Biochim Biophys Acta 1401:129–145PubMedCrossRefGoogle Scholar
  53. Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10:839–850PubMedCrossRefGoogle Scholar
  54. Maldonado-Baez L, Wendland B (2006) Endocytic adaptors: recruiters, coordinators and regulators. Trends Cell Biol 16:505–513PubMedCrossRefGoogle Scholar
  55. Martina JA, Bonangelino CJ, Aguilar RC, Bonifacino JS (2001) Stonin 2: an adaptor-like protein that interacts with components of the endocytic machinery. J Cell Biol 153:1111–1120PubMedCrossRefGoogle Scholar
  56. Maycox PR, Link E, Reetz A, Morris SA, Jahn R (1992) Clathrin-coated vesicles in nervous tissue are involved primarily in synaptic vesicle recycling. J Cell Biol 118:1379–1388PubMedCrossRefGoogle Scholar
  57. McNiven MA (1998) Dynamin: a molecular motor with pinchase action. Cell 94:151–14PubMedCrossRefGoogle Scholar
  58. Mitsunari T, Nakatsu F, Shioda N, Love PE, Grinberg A, Bonifacino JS, Ohno H (2005) Clathrin adaptor AP-2 is essential for early embryonal development. Mol Cell Biol 25:9318–9323PubMedCrossRefGoogle Scholar
  59. Morrow IC, Parton RG (2005) Flotillins and the PHB domain protein family: rafts, worms and anaesthetics. Traffic 6:725–740PubMedCrossRefGoogle Scholar
  60. Motley A, Bright NA, Seaman MN, Robinson MS (2003) Clathrin-mediated endocytosis in AP-2-depleted cells. J Cell Biol 162:909–918PubMedCrossRefGoogle Scholar
  61. Motley AM, Berg N, Taylor MJ, Sahlender DA, Hirst J, Owen DJ, Robinson MS (2006) Functional analysis of AP-2 alpha and mu2 subunits. Mol Biol Cell 17:5298–5308PubMedCrossRefGoogle Scholar
  62. Mukherjee S, Ghosh RN, Maxfield FR (1997) Endocytosis. Physiol Rev 77:759–803PubMedGoogle Scholar
  63. Nesterov A, Carter RE, Sorkina T, Gill GN, Sorkin A (1999) Inhibition of the receptor-binding function of clathrin adaptor protein AP-2 by dominant-negative mutant mu2 subunit and its effects on endocytosis. EMBO J 18:2489–2499PubMedCrossRefGoogle Scholar
  64. Newmyer SL, Christensen A, Sever S (2003) Auxilin-dynamin interactions link the uncoating ATPase chaperone machinery with vesicle formation. Dev Cell 4:929–940PubMedCrossRefGoogle Scholar
  65. Ochoa GC, Slepnev VI, Neff L, Ringstad N, Takei K, Daniell L, Kim W, Cao H, McNiven M, Baron R, De Camilli P (2000) A functional link between dynamin and the actin cytoskeleton at podosomes. J Cell Biol 150:377–389PubMedCrossRefGoogle Scholar
  66. Ohno H, Stewart J, Fournier MC, Bosshart H, Rhee I, Miyatake S, Saito T, Gallusser A, Kirchhausen T, Bonifacino JS (1995) Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science 269:1872–1875PubMedCrossRefGoogle Scholar
  67. Owen DJ, Evans PR (1998) A structural explanation for the recognition of tyrosine-based endocytotic signals. Science 282:1327–1332PubMedCrossRefGoogle Scholar
  68. Owen DJ, Luzio JP (2000) Structural insights into clathrin-mediated endocytosis. Curr Opin Cell Biol 12:467–474PubMedCrossRefGoogle Scholar
  69. Owen DJ, Vallis Y, Noble ME, Hunter JB, Dafforn TR, Evans PR, McMahon HT (1999) A structural explanation for the binding of multiple ligands by the alpha-adaptin appendage domain. Cell 97:805–815PubMedCrossRefGoogle Scholar
  70. Owen DJ, Setiadi H, Evans PR, McEver RP, Green SA (2001) A third specificity-determining site in mu 2 adaptin for sequences upstream of Yxx phi sorting motifs. Traffic 2:105–110PubMedCrossRefGoogle Scholar
  71. Perera RM, Zoncu R, Lucast L, De Camilli P, Toomre D (2006) Two synaptojanin 1 isoforms are recruited to clathrin-coated pits at different stages. Proc Natl Acad Sci USA 103: 19332–19337PubMedCrossRefGoogle Scholar
  72. Praefcke GJ, Ford MG, Schmid EM, Olesen LE, Gallop JL, Peak-Chew SY, Vallis Y, Babu MM, Mills IG, McMahon HT (2004) Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis. EMBO J 23:4371–4383PubMedCrossRefGoogle Scholar
  73. Puthenveedu MA, von Zastrow M (2006) Cargo regulates clathrin-coated pit dynamics. Cell 127: 113–124PubMedCrossRefGoogle Scholar
  74. Ricotta D, Conner SD, Schmid SL, von Figura K, Honing S (2002) Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals. J Cell Biol 156:791–795PubMedCrossRefGoogle Scholar
  75. Ritter B, Philie J, Girard M, Tung EC, Blondeau F, McPherson PS (2003) Identification of a family of endocytic proteins that define a new alpha-adaptin ear-binding motif. EMBO Rep 4: 1089–1095PubMedCrossRefGoogle Scholar
  76. Robinson MS, Bonifacino JS (2001) Adaptor-related proteins. Curr Opin Cell Biol 13:444–453PubMedCrossRefGoogle Scholar
  77. Rohde G, Wenzel D, Haucke V (2002) A phosphatidylinositol (4,5)-bisphosphate binding site within mu2-adaptin regulates clathrin-mediated endocytosis. J Cell Biol 158:209–214PubMedCrossRefGoogle Scholar
  78. Roux A, Uyhazi K, Frost A, De Camilli P (2006) GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission. Nature 441:528–531PubMedCrossRefGoogle Scholar
  79. Sandvig K, Olsnes S, Petersen OW, van Deurs B (1987) Acidification of the cytosol inhibits endocytosis from coated pits. J Cell Biol 105:679–689PubMedCrossRefGoogle Scholar
  80. Schweizer FE, Ryan TA (2006) The synaptic vesicle: cycle of exocytosis and endocytosis. Curr Opin Neurobiol 16:298–304PubMedCrossRefGoogle Scholar
  81. Sorkin A, Carpenter G (1993) Interaction of activated EGF receptors with coated pit adaptins. Science 261:612–615PubMedCrossRefGoogle Scholar
  82. Stang E, Blystad FD, Kazazic M, Bertelsen V, Brodahl T, Raiborg C, Stenmark H, Madshus IH (2004) Cbl-dependent ubiquitination is required for progression of EGF receptors into clathrin-coated pits. Mol Biol Cell 15:3591–3604PubMedCrossRefGoogle Scholar
  83. Stimson DT, Estes PS, Rao S, Krishnan KS, Kelly LE, Ramaswami M (2001) Drosophila stoned proteins regulate the rate and fidelity of synaptic vesicle internalization. J Neurosci 21: 3034–3044PubMedGoogle Scholar
  84. Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M, Riedel D, Urlaub H, Schenck S, Brugger B, Ringler P, Muller SA, Rammner B, Grater F, Hub JS, De Groot BL, Mieskes G, Moriyama Y, Klingauf J, Grubmuller H, Heuser J, Wieland F, Jahn R (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846PubMedCrossRefGoogle Scholar
  85. Takei K, Haucke V (2001) Clathrin-mediated endocytosis: membrane factors pull the trigger. Trends Cell Biol 11:385–391PubMedCrossRefGoogle Scholar
  86. Thompson HM, Cao H, Chen J, Euteneuer U, McNiven MA (2004) Dynamin 2 binds gamma-tubulin and participates in centrosome cohesion. Nat Cell Biol 6:335–342PubMedCrossRefGoogle Scholar
  87. Traub LM (2003) Sorting it out: AP-2 and alternate clathrin adaptors in endocytic cargo selection. J Cell Biol 163:203–208PubMedCrossRefGoogle Scholar
  88. Traub LM (2005) Common principles in clathrin-mediated sorting at the Golgi and the plasma membrane. Biochim Biophys Acta 1744:415–437PubMedCrossRefGoogle Scholar
  89. Varnai P, Thyagarajan B, Rohacs T, Balla T (2006) Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells. J Cell Biol 175:377–382PubMedCrossRefGoogle Scholar
  90. Walther K, Diril MK, Jung N, Haucke V (2004) Functional dissection of the interactions of stonin 2 with the adaptor complex AP-2 and synaptotagmin. Proc Natl Acad Sci USA 101:964–969PubMedCrossRefGoogle Scholar
  91. Wang LH, Rothberg KG, Anderson RG (1993) Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J Cell Biol 123:1107–1117PubMedCrossRefGoogle Scholar
  92. Wang H, Traub LM, Weixel KM, Hawryluk MJ, Shah N, Edinger RS, Perry CJ, Kester L, Butterworth MB, Peters KW, Kleyman TR, Frizzell RA, Johnson JP (2006) Clathrin-mediated endocytosis of the epithelial sodium channel. Role of epsin. J Biol Chem 281:14129–14135PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • C. Rodemer
    • 1
    • 2
  • V. Haucke
    • 3
  1. 1.Department of Membrane BiochemistryBerlin
  2. 2.Institute of Chemistry & BiochemistryFreie Universität BerlinBerlinGermany
  3. 3.Institute of Chemistry & Biochemistry, Department of Membrane BiochemistryFreie Universität BerlinBerlinGermany

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