Clathrin-Mediated Endocytosis

  • Alexander SorkinEmail author
  • Manojkumar A. PuthenveeduEmail author


Clathrin-mediated endocytosis is the main portal of entry into the cell for many soluble and membrane molecules. Clathrin-coated vesicles are formed from the plasma membrane in a sequence of coordinated protein-lipid and protein-protein interactions, starting with adaptor-mediated recruitment of clathrin to the membrane, proceeding to clathrin polymerization and assembly into deeply curved coated buds, and ending with the dynamin-dependent scission of a coated vesicle. Clathrin coats trap and concentrate endocytic cargo by using a multitude of adaptor proteins that recognize specific sequence motifs in the cytosolic domains of receptors and other transmembrane cargo molecules. Endocytic cargo that is concentrated in this manner, such as signaling receptors, may regulate the stability, size, and dynamics of individual clathrin coats and thereby influence endocytosis.


Clathrin Heavy Chain Cargo Molecule Proximal Domain Clathrin Coat Clathrin Assembly 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Supported by NIH grants CA089151 (AS), DA014204 (AS) and DA024698 (MAP).


  1. 1.
    Howes MT, Mayor S, Parton RG (2010) Molecules, mechanisms, and cellular roles of clathrin-­independent endocytosis. Curr Opin Cell Biol 22(4):519–527PubMedCrossRefGoogle Scholar
  2. 2.
    McMahon HT, Boucrot E (2011) Molecular mechanism and physiological functions of clathrin-­mediated endocytosis. Nat Rev Mol Cell Biol 12(8):517–533PubMedCrossRefGoogle Scholar
  3. 3.
    Lund KA, Opresko LK, Strarbuck C, Walsh BJ, Wiley HS (1990) Quantitative analysis of the endocytic system involved in hormone-induced receptor internalization. J Biol Chem 265:15713–15723PubMedGoogle Scholar
  4. 4.
    Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902. doi: 10.1146/annurev.biochem.78.081307.110540 PubMedCrossRefGoogle Scholar
  5. 5.
    Young A (2007) Structural insights into the clathrin coat. Semin Cell Dev Biol 18(4):448–458PubMedCrossRefGoogle Scholar
  6. 6.
    Fotin A, Cheng Y, Sliz P, Grigorieff N, Harrison SC, Kirchhausen T, Walz T (2004) Molecular model for a complete clathrin lattice from electron cryomicroscopy. Nature 432(7017):573–579PubMedCrossRefGoogle Scholar
  7. 7.
    Kirchhausen T, Harrison SC (1981) Protein organization in clathrin trimers. Cell 23(3):755–761PubMedCrossRefGoogle Scholar
  8. 8.
    Undewickell E, Branton D (1981) Assembly units of clathrin coats. Nature 289:420–422CrossRefGoogle Scholar
  9. 9.
    Ybe JA, Brodsky FM, Hofmann K, Lin K, Liu SH, Chen L, Earnest TN, Fletterick RJ, Hwang PK (1999) Clathrin self-assembly is mediated by a tandemly repeated superhelix. Nature 399(6734):371–375PubMedCrossRefGoogle Scholar
  10. 10.
    Kirchhausen T, Harrison SC (1984) Structural domains of clathrin heavy chains. J Cell Biol 718 99(5):1725–1734PubMedCrossRefGoogle Scholar
  11. 11.
    Fotin A, Cheng Y, Grigorieff N, Walz T, Harrison SC, Kirchhausen T (2004) Structure of an auxilin-bound clathrin coat and its implications for the mechanism of uncoating. Nature 432(7017):649–653PubMedCrossRefGoogle Scholar
  12. 12.
    ter Haar E, Musacchio A, Harrison SC, Kirchhausen T (1998) Atomic structure of clathrin: a β propeller terminal domain joins an α zigzag linker. Cell 95:563–575PubMedCrossRefGoogle Scholar
  13. 13.
    Miele AE, Watson PJ, Evans PR, Traub LM, Owen DJ (2004) Two distinct interaction motifs in amphiphysin bind two independent sites on the clathrin terminal domain beta-propeller. Nat Struct Mol Biol 11(3):242–248PubMedCrossRefGoogle Scholar
  14. 14.
    Chen CY, Reese ML, Hwang PK, Ota N, Agard D, Brodsky FM (2002) Clathrin light and heavy chain interface: alpha-helix binding superhelix loops via critical tryptophans. EMBO J 21(22):6072–6082PubMedCrossRefGoogle Scholar
  15. 15.
    Nathke IS, Heuser J, Lupas A, Stock J, Turck CW, Brodsky FM (1992) Folding and trimerization of clathrin subunits at the triskelion hub. Cell 68(5):899–910PubMedCrossRefGoogle Scholar
  16. 16.
    Ungewickell E (1983) Biochemical and immunological studies on clathrin light chains and their binding sites on clathrin triskelions. EMBO J 2(8):1401–1408PubMedGoogle Scholar
  17. 17.
    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(16):16657–16661PubMedCrossRefGoogle Scholar
  18. 18.
    Pishvaee B, Munn A, Payne GS (1997) A novel structural model for regulation of clathrin function. EMBO J 16(9):2227–2239PubMedCrossRefGoogle Scholar
  19. 19.
    Boulant S, Kural C, Zeeh J-C, Ubelmann F, Kirchhausen T (2011) Actin dynamics counteract membrane tension during clathrin-mediated endocytosis. Nat Cell Biol 13(9):1124–1131PubMedCrossRefGoogle Scholar
  20. 20.
    Wilbur JD, Chen CY, Manalo V, Hwang PK, Fletterick RJ, Brodsky FM (2008) Actin binding by Hip1 (huntingtin-interacting protein 1) and Hip1R (hip1-related protein) is regulated by clathrin light chain. J Biol Chem 283(47):32870–32879PubMedCrossRefGoogle Scholar
  21. 21.
    Chen H, De Camilli P (2005) The association of epsin with ubiquitinated cargo along the endocytic pathway is negatively regulated by its interaction with clathrin. Proc Natl Acad Sci U S A 102(8):2766–2771PubMedCrossRefGoogle Scholar
  22. 22.
    Engqvist-Goldstein AE, Warren RA, Kessels MM, Keen JH, Heuser J, Drubin DG (2001) The actin-binding protein Hip1R associates with clathrin during early stages of endocytosis and promotes clathrin assembly in vitro. J Cell Biol 154(6):1209–1223PubMedCrossRefGoogle Scholar
  23. 23.
    Ferreira F, Foley M, Cooke A, Cunningham M, Smith G, Woolley R, Henderson G, Kelly E, Mundell S, Smythe E (2012) Endocytosis of g protein-coupled receptors is regulated by clathrin light chain phosphorylation. Curr Biol 22(15):1361–1370PubMedCrossRefGoogle Scholar
  24. 24.
    Keen JH, Willingham MC, Pastan I (1981) Clathrin and coated vesicle proteins immunological characterization. J Biol Chem 256(5):2538–2544PubMedGoogle Scholar
  25. 25.
    Pearse BM, Robinson MS (1984) Purification and properties of 100-kd proteins from coated vesicles and their reconstitution with clathrin. EMBO J 3(9):1951–1957PubMedGoogle Scholar
  26. 26.
    Collins BM, McCoy AJ, Kent HM, Evans PR, Owen DJ (2002) Molecular architecture and functional model of the endocytic AP2 complex. Cell 109(4):523–535PubMedCrossRefGoogle Scholar
  27. 27.
    Heuser JE, Keen J (1988) Deep-etch visualization of proteins involved in clathrin assembly. J Cell Biol 107(3):877–886PubMedCrossRefGoogle Scholar
  28. 28.
    Zaremba S, Keen JH (1983) Assembly polypeptides from coated vesicles mediate reassembly of unique clathrin coats. J Cell Biol 97(5 pt 1):1339–1347PubMedCrossRefGoogle Scholar
  29. 29.
    Owen DJ, Collins BM, Evans PR (2004) Adaptors for clathrin coats: structure and function. Annu Rev Cell Dev Biol 20:153–191PubMedCrossRefGoogle Scholar
  30. 30.
    Gaidarov I, Chen Q, Falck JR, Reddy KK, Keen JH (1996) A functional phosphatidylinositol 3,4,5-trisphosphate/phosphoinositide binding domain in the clathrin adaptor AP-2 alpha subunit. Implications for the endocytic pathway. J Biol Chem 271(34):20922–20929PubMedCrossRefGoogle Scholar
  31. 31.
    Jackson LP, Kelly BT, McCoy AJ, Gaffry T, James LC, Collins BM, Höning S, Evans PR, Owen DJ (2010) A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex. Cell 141(7):1220–1229PubMedCrossRefGoogle Scholar
  32. 32.
    Kelly BT, McCoy AJ, Spate K, Miller SE, Evans PR, Honing S, Owen DJ (2008) A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex. Nature 456(7224):976–979PubMedCrossRefGoogle Scholar
  33. 33.
    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(2):209–214PubMedCrossRefGoogle Scholar
  34. 34.
    Ahle S, Ungewickell E (1986) Purification and properties of a new clathrin assembly protein. EMBO J 5(12):3143–3149PubMedGoogle Scholar
  35. 35.
    Chen H, Fre S, Slepnev VI, Capua MR, Takei K, Butler MH, Di Fiore PP, De Camilli P (1998) Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature 394(6695):793–797PubMedCrossRefGoogle Scholar
  36. 36.
    Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT (2001) Simultaneous binding of Ptdins (4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science 291(5506):1051–1055PubMedCrossRefGoogle Scholar
  37. 37.
    Tebar F, Bohlander S, Sorkin A (1999) Interactions of clathrin assembly lymphoid myeloid (CALM) protein with clathrin and its impact on endocytosis. Mol Biol Cell 10:2687–2702PubMedGoogle Scholar
  38. 38.
    Dannhauser PN, Ungewickell EJ (2012) Reconstitution of clathrin-coated bud and vesicle formation with minimal components. Nat Cell Biol 14(6):634–639PubMedCrossRefGoogle Scholar
  39. 39.
    Hinrichsen L, Meyerholz A, Groos S, Ungewickell EJ (2006) Bending a membrane: how clathrin affects budding. Proc Natl Acad Sci U S A 103(23):8715–8720PubMedCrossRefGoogle Scholar
  40. 40.
    Cocucci E, Aguet F, Boulant S, Kirchhausen T (2012) The first five seconds in the life of a clathrin-coated pit. Cell 150(3):495–507PubMedCrossRefGoogle Scholar
  41. 41.
    Henne WM, Boucrot E, Meinecke M, Evergren E, Vallis Y, Mittal R, McMahon HT (2010) FCHo proteins are nucleators of clathrin-mediated endocytosis. Science 328(5983):1281–1284PubMedCrossRefGoogle Scholar
  42. 42.
    Nunez D, Antonescu C, Mettlen M, Liu A, Schmid SL, Loerke D, Danuser G (2011) Hotspots organize clathrin-mediated endocytosis by efficient recruitment and retention of nucleating resources. Traffic 12(12):1868–1878PubMedCrossRefGoogle Scholar
  43. 43.
    Umasankar PK, Sanker S, Thieman JR, Chakraborty S, Wendland B, Tsang M, Traub LM (2012) Distinct and separable activities of the endocytic clathrin-coat components fcho1/2 and AP-2 in developmental patterning. Nat Cell Biol 14(5):488–501PubMedCrossRefGoogle Scholar
  44. 44.
    Mulkearns EE, Cooper JA (2012) FCH domain only-2 organizes clathrin-coated structures and interacts with disabled-2 for low-density lipoprotein receptor endocytosis. Mol Biol Cell 23(7):1330–1342PubMedCrossRefGoogle Scholar
  45. 45.
    Teckchandani A, Mulkearns EE, Randolph TW, Toida N, Cooper JA (2012) The clathrin adaptor dab2 recruits EH domain scaffold proteins to regulate integrin beta1 endocytosis. Mol Biol Cell 23(15):2905–2916PubMedCrossRefGoogle Scholar
  46. 46.
    Tebar F, Sorkina T, Sorkin A, Ericsson M, Kirchhausen T (1996) Eps15 is a component of clathrin-coated pits and vesicles and is located at the rim of coated pits. J Biol Chem 271(46):28727–28730PubMedCrossRefGoogle Scholar
  47. 47.
    Traub LM (2009) Tickets to ride: selecting cargo for clathrin-regulated internalization. Nat Rev Mol Cell Biol 10(9):583–596PubMedCrossRefGoogle Scholar
  48. 48.
    Claing A, Laporte SA, Caron MG, Lefkowitz RJ (2002) Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins. Prog Neurobiol 66(2):61–79PubMedCrossRefGoogle Scholar
  49. 49.
    Kim Y-M, Benovic JL (2002) Differential roles of arrestin-2 interaction with clathrin and adaptor protein 2 in G protein-coupled receptor trafficking. J Biol Chem 277(34):30760–30768PubMedCrossRefGoogle Scholar
  50. 50.
    Ehrlich M, Boll W, Van Oijen A, Hariharan R, Chandran K, Nibert ML, Kirchhausen T (2004) Endocytosis by random initiation and stabilization of clathrin-coated pits. Cell 118(5):591–605PubMedCrossRefGoogle Scholar
  51. 51.
    Kazazic M, Bertelsen V, Pedersen KW, Vuong TT, Grandal MV, Rodland MS, Traub LM, Stang E, Madshus IH (2009) Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits. Traffic 10(2):235–245PubMedCrossRefGoogle Scholar
  52. 52.
    Ford MG, Mills IG, Peter BJ, Vallis Y, Praefcke GJ, Evans PR, McMahon HT (2002) Curvature of clathrin-coated pits driven by epsin. Nature 419(6905):361–366PubMedCrossRefGoogle Scholar
  53. 53.
    Peter BJ, Kent HM, Mills IG, Vallis Y, Butler PJ, Evans PR, McMahon HT (2004) BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science 303(5657):495–499PubMedCrossRefGoogle Scholar
  54. 54.
    Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, Di Fiore PP, Polo S (2005) From the cover: clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci U S A 102(8):2760–2765PubMedCrossRefGoogle Scholar
  55. 55.
    Ferguson SM, De Camilli P (2012) Dynamin, a membrane-remodelling gtpase. Nat Rev Mol Cell Biol 13(2):75–88PubMedGoogle Scholar
  56. 56.
    Schmid SL, Frolov VA (2011) Dynamin: functional design of a membrane fission catalyst. Annu Rev Cell Dev Biol 27(3):1–27Google Scholar
  57. 57.
    Takei K, McPherson PS, Schmid SL, De Camilli P (1995) Tubular membrane invaginations coated by dynamin rings are induced by GTP-gamma S in nerve terminals [see comments]. Nature 374(6518):186–190PubMedCrossRefGoogle Scholar
  58. 58.
    Bashkirov PV, Akimov SA, Evseev AI, Schmid SL, Zimmerberg J, Frolov VA (2008) GTPase cycle of dynamin is coupled to membrane squeeze and release, leading to spontaneous fission. Cell 135(7):1276–1286PubMedCrossRefGoogle Scholar
  59. 59.
    Boucrot E, Pick A, Camdere G, Liska N, Evergren E, McMahon HT, Kozlov MM (2012) Membrane fission is promoted by insertion of amphipathic helices and is restricted by crescent BAR domains. Cell 149(1):124–136PubMedCrossRefGoogle Scholar
  60. 60.
    Shevchuk AI, Novak P, Taylor M, Diakonov IA, Ziyadeh-Isleem A, Bitoun M, Guicheney P et al (2012) An alternative mechanism of clathrin-coated pit closure revealed by ion conductance microscopy. J Cell Biol 197(4):499–508PubMedCrossRefGoogle Scholar
  61. 61.
    Taylor MJ, Perrais D, Merrifield CJ (2011) A high precision survey of the molecular dynamics of mammalian clathrin-mediated endocytosis. PLoS Biol 9(3):e1000604PubMedCrossRefGoogle Scholar
  62. 62.
    Taylor MJ, Lampe M, Merrifield CJ (2012) A feedback loop between dynamin and actin recruitment during clathrin-mediated endocytosis. PLoS Biol 10(4):e1001302PubMedCrossRefGoogle Scholar
  63. 63.
    Schlossman DM, Schmid SL, Braell WA, Rothman JE (1984) An enzyme that removes clathrin coats: purification of an uncoating atpase. J Cell Biol 99(2):723–733PubMedCrossRefGoogle Scholar
  64. 64.
    Ungewickell E, Ungewickell H, Holstein SE, Lindner R, Prasad K, Barouch W, Martin B, Greene LE, Eisenberg E (1995) Role of auxilin in uncoating clathrin-coated vesicles. Nature 378(6557):632–635PubMedCrossRefGoogle Scholar
  65. 65.
    Scheele U, Kalthoff C, Ungewickell E (2001) Multiple interactions of auxilin 1 with clathrin and the AP-2 adaptor complex. J Biol Chem 276(39):36131–36138PubMedCrossRefGoogle Scholar
  66. 66.
    Nakatsu F, Perera RM, Lucast L, Zoncu R, Domin J, Gertler FB, Toomre D, De Camilli P (2010) The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics. J Cell Biol 190(3):307–315PubMedCrossRefGoogle Scholar
  67. 67.
    Schuske KR, Richmond JE, Matthies DS, Davis WS, Runz S, Rube DA, van der Bliek AM, Jorgensen EM (2003) Endophilin is required for synaptic vesicle endocytosis by localizing synaptojanin. Neuron 40(4):749–762PubMedCrossRefGoogle Scholar
  68. 68.
    McPherson PS, Garcia EP, Slepnev VI, David C, Zhang X, Grabs D, Sossin WS, Bauerfeind R, Nemoto Y, De Camilli P (1996) A presynaptic inositol-5-phosphatase. Nature 379(6563):353–357PubMedCrossRefGoogle Scholar
  69. 69.
    Erdmann KS, Mao Y, McCrea HJ, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P (2007) A role of the lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell 13(3):377–390PubMedCrossRefGoogle Scholar
  70. 70.
    Sorkin A, von Zastrow M (2009) Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 10(9):609–622PubMedCrossRefGoogle Scholar
  71. 71.
    Rao Y, Rückert C, Saenger W, Haucke V (2012) The early steps of endocytosis: from cargo selection to membrane deformation. Eur J Cell Biol 91(4):226–233PubMedCrossRefGoogle Scholar
  72. 72.
    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(5232):1872–1875PubMedCrossRefGoogle Scholar
  73. 73.
    Owen DJ, Evans PR (1998) A structural explanation for the recognition of tyrosine-based endocytotic signals. Science 282(5392):1327–1332PubMedCrossRefGoogle Scholar
  74. 74.
    Kittler JT, Chen G, Kukhtina V, Vahedi-Faridi A, Zhenglin G, Tretter V, Smith KR et al (2008) Regulation of synaptic inhibition by phospho-dependent binding of the AP2 complex to a YECL motif in the GABAA receptor gamma2 subunit. Proc Natl Acad Sci U S A 105(9):3616–3621PubMedCrossRefGoogle Scholar
  75. 75.
    Rollason R, Korolchuk V, Hamilton C, Schu P, Banting G (2007) Clathrin-mediated endocytosis of a lipid-raft-associated protein is mediated through a dual tyrosine motif. J Cell Sci 120(pt 21):3850–3858PubMedCrossRefGoogle Scholar
  76. 76.
    Masuyama N, Kuronita T, Tanaka R, Muto T, Hirota Y, Takigawa A, Fujita H, Aso Y, Amano J, Tanaka Y (2009) HM1.24 is internalized from lipid rafts by clathrin-mediated endocytosis through interaction with alpha-adaptin. J Biol Chem 284(23):15927–15941PubMedCrossRefGoogle Scholar
  77. 77.
    Höning S, Ricotta D, Krauss M, Späte 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(5):519–531PubMedCrossRefGoogle Scholar
  78. 78.
    Conner SD, Schmid SL (2002) Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. J Cell Biol 156(5):921–929PubMedCrossRefGoogle Scholar
  79. 79.
    Conner SD, Schröter T, Schmid SL (2003) AAK1-mediated micro2 phosphorylation is stimulated by assembled clathrin. Traffic 4(12):885–890PubMedCrossRefGoogle Scholar
  80. 80.
    Henderson DM, Conner SD (2007) A novel AAK1 splice variant functions at multiple steps of the endocytic pathway. Mol Biol Cell 18(7):2698–2706PubMedCrossRefGoogle Scholar
  81. 81.
    Jackson AP, Flett A, Smythe C, Hufton L, Wettey FR, Smythe E (2003) Clathrin promotes incorporation of cargo into coated pits by activation of the AP2 adaptor micro2 kinase. J Cell Biol 163(2):231–236PubMedCrossRefGoogle Scholar
  82. 82.
    Olusanya O, Andrews PD, Swedlow JR, Smythe E (2001) Phosphorylation of threonine 156 of the mu2 subunit of the AP2 complex is essential for endocytosis in vitro and in vivo. Curr Biol 11(11):896–900PubMedCrossRefGoogle Scholar
  83. 83.
    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(5):791–795PubMedCrossRefGoogle Scholar
  84. 84.
    Shiratori T, Miyatake S, Ohno H, Nakaseko C, Isono K, Bonifacino JS, Saito T (1997) Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2. Immunity 6(5):583–589PubMedCrossRefGoogle Scholar
  85. 85.
    Jurd R, Tretter V, Walker J, Brandon NJ, Moss SJ (2010) Fyn kinase contributes to tyrosine phosphorylation of the GABA (A) receptor gamma2 subunit. Mol Cell Neurosci 44(2):129–134, Google Scholar
  86. 86.
    Goh LK, Huang F, Kim W, Gygi S, Sorkin A (2010) Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. J Cell Biol 189(5):871–883PubMedCrossRefGoogle Scholar
  87. 87.
    Huang F, Jiang X, Sorkin A (2003) Tyrosine phosphorylation of the beta2 subunit of clathrin adaptor complex AP-2 reveals the role of a di-leucine motif in the epidermal growth factor receptor trafficking. J Biol Chem 278(44):43411–43417PubMedCrossRefGoogle Scholar
  88. 88.
    Sorkin A, Mazzotti M, Sorkina T, Scotto L, Beguinot L (1996) Epidermal growth factor receptor interaction with clathrin adaptors is mediated by the tyr974-containing internalization motif. J Biol Chem 271(23):13377–13384PubMedCrossRefGoogle Scholar
  89. 89.
    Haucke V, De Camilli P (1999) AP-2 recruitment to synaptotagmin stimulated by tyrosine-­based endocytic motifs. Science 285(5431):1268–1271PubMedCrossRefGoogle Scholar
  90. 90.
    Lee I, Doray B, Govero J, Kornfeld S (2008) Binding of cargo sorting signals to AP-1 enhances its association with ADP ribosylation factor 1-GTP. J Cell Biol 180(3):467–472PubMedCrossRefGoogle Scholar
  91. 91.
    Ishiyama N, Lee S-H, Liu S, Li G-Y, Smith MJ, Reichardt LF, Ikura M (2010) Dynamic and static interactions between p120 catenin and e-cadherin regulate the stability of cell-cell adhesion. Cell 141(1):117–128PubMedCrossRefGoogle Scholar
  92. 92.
    Davis MA, Ireton RC, Reynolds AB (2003) A core function for p120-catenin in cadherin turnover. J Cell Biol 163(3):525–534PubMedCrossRefGoogle Scholar
  93. 93.
    Miyashita Y, Ozawa M (2007) Increased internalization of p120-uncoupled e-cadherin and a requirement for a dileucine motif in the cytoplasmic domain for endocytosis of the protein. J Biol Chem 282(15):11540–11548PubMedCrossRefGoogle Scholar
  94. 94.
    Sato K, Watanabe T, Wang S, Kakeno M, Matsuzawa K, Matsui T, Yokoi K et al (2011) Numb controls e-cadherin endocytosis through p120 catenin with apkc. Mol Biol Cell 22(17):3103–3119PubMedCrossRefGoogle Scholar
  95. 95.
    Chen WJ, Goldstein JL, Brown MS (1990) NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 265(6):3116–3123PubMedGoogle Scholar
  96. 96.
    Davis CG, Lehrman MA, Russell DW, Anderson RG, Brown MS, Goldstein JL (1986) The J.D. Mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell 45(1):15–24PubMedCrossRefGoogle Scholar
  97. 97.
    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(46):45160–45170PubMedCrossRefGoogle Scholar
  98. 98.
    Motley A, Bright NA, Seaman MNJ, Robinson MS (2003) Clathrin-mediated endocytosis in ap-2-depleted cells. J Cell Biol 162(5):909–918PubMedCrossRefGoogle Scholar
  99. 99.
    Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S et al (2001) Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 292(5520):1394–1398PubMedCrossRefGoogle Scholar
  100. 100.
    Mishra SK, Keyel PA, Hawryluk MJ, Agostinelli NR, Watkins SC, Traub LM (2002) Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor. EMBO J 21(18):4915–4926PubMedCrossRefGoogle Scholar
  101. 101.
    Morris SM, Cooper JA (2001) Disabled-2 colocalizes with the LDLR in clathrin-coated pits and interacts with AP-2. Traffic 2(2):111–123PubMedCrossRefGoogle Scholar
  102. 102.
    Santolini E, Puri C, Salcini AE, Gagliani MC, Pelicci PG, Tacchetti C, Di Fiore PP (2000) Numb is an endocytic protein. J Cell Biol 151(6):1345–1352PubMedCrossRefGoogle Scholar
  103. 103.
    Chetrit D, Ziv N, Ehrlich M (2009) Dab2 regulates clathrin assembly and cell spreading. Biochem J 418(3):701–715PubMedCrossRefGoogle Scholar
  104. 104.
    Eden ER, Sun X-M, Patel DD, Soutar AK (2007) Adaptor protein disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia. Hum Mol Genet 16(22):2751–2759PubMedCrossRefGoogle Scholar
  105. 105.
    Keyel PA, Mishra SK, Roth R, Heuser JE, Watkins SC, Traub LM (2006) A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors. Mol Biol Cell 17(10):4300PubMedCrossRefGoogle Scholar
  106. 106.
    Maurer ME, Cooper JA (2006) The adaptor protein dab2 sorts LDL receptors into coated pits independently of AP-2 and ARH. J Cell Sci 119(pt 20):4235–4246PubMedCrossRefGoogle Scholar
  107. 107.
    Uhlik MT, Temple B, Bencharit S, Kimple AJ, Siderovski DP, Johnson GL (2005) Structural and evolutionary division of phosphotyrosine binding (PTB) domains. J Mol Biol 345(1):1–20PubMedCrossRefGoogle Scholar
  108. 108.
    Stolt PC, Bock HH (2006) Modulation of lipoprotein receptor functions by intracellular adaptor proteins. Cell Signal 18(10):1560–1571PubMedCrossRefGoogle Scholar
  109. 109.
    Howell BW, Lanier LM, Frank R, Gertler FB, Cooper JA (1999) The disabled 1 phosphotyrosine-­binding domain binds to the internalization signals of transmembrane glycoproteins and to phospholipids. Mol Cell Biol 19(7):5179–5188PubMedGoogle Scholar
  110. 110.
    Dvir H, Shah M, Girardi E, Guo L, Farquhar MG, Zajonc DM (2012) Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail. Proc Natl Acad Sci U S A 109(18):6916–6921PubMedCrossRefGoogle Scholar
  111. 111.
    Edeling MA, Mishra SK, Keyel PA, Steinhauser AL, Collins BM, Roth R, Heuser JE, Owen DJ, Traub LM (2006) Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly. Dev Cell 10(3):329–342PubMedCrossRefGoogle Scholar
  112. 112.
    Berdnik D, Török T, González-Gaitán M, Knoblich JA (2002) The endocytic protein alpha-­adaptin is required for numb-mediated asymmetric cell division in drosophila. Dev Cell 3(2):221–231PubMedCrossRefGoogle Scholar
  113. 113.
    Kyriazis GA, Wei Z, Vandermey M, Jo D-G, Xin O, Mattson MP, Chan SL (2008) Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis. J Biol Chem 283(37):25492–25502PubMedCrossRefGoogle Scholar
  114. 114.
    Sorensen EB, Conner SD (2008) AAK1 regulates numb function at an early step in clathrin-­mediated endocytosis. Traffic 9(10):1791–1800PubMedCrossRefGoogle Scholar
  115. 115.
    Nishimura T, Kaibuchi K (2007) Numb controls integrin endocytosis for directional cell migration with apkc and PAR-3. Dev Cell 13(1):15–28PubMedCrossRefGoogle Scholar
  116. 116.
    Tokumitsu H, Hatano N, Yokokura S, Sueyoshi Y, Nozaki N, Kobayashi R (2006) Phosphorylation of numb regulates its interaction with the clathrin-associated adaptor AP-2. FEBS Lett 580(24):5797–5801PubMedCrossRefGoogle Scholar
  117. 117.
    Schmid EM, Ford MG, Burtey A, Praefcke GJ, Peak-Chew SY, Mills IG, Benmerah A, McMahon HT (2006) Role of the AP2 beta-appendage hub in recruiting partners for ­clathrin-­coated vesicle assembly. PLoS Biol 4(9):e262, PubMedCrossRefGoogle Scholar
  118. 118.
    Südhof TC, Rothman JE (2009) Membrane fusion: grappling with SNARE and SM proteins. Science 323(5913):474–477PubMedCrossRefGoogle Scholar
  119. 119.
    Koo SJ, Markovic S, Puchkov D, Mahrenholz CC, Beceren-Braun F, Maritzen T, Dernedde J, Volkmer R, Oschkinat H, Haucke V (2011) SNARE motif-mediated sorting of synaptobrevin by the endocytic adaptors clathrin assembly lymphoid myeloid leukemia (CALM) and AP180 at synapses. Proc Natl Acad Sci U S A 108(33):13540–13545PubMedCrossRefGoogle Scholar
  120. 120.
    Miller SE, Sahlender DA, Graham SC, Honing S, Robinson MS, Peden AA, Owen DJ (2011) The molecular basis for the endocytosis of small r-snares by the clathrin adaptor CALM. Cell 147(5):1118–1131PubMedCrossRefGoogle Scholar
  121. 121.
    Miller SE, Collins BM, McCoy AJ, Robinson MS, Owen DJ (2007) A snare-adaptor interaction is a new mode of cargo recognition in clathrin-coated vesicles. Nature 450(7169):570–574PubMedCrossRefGoogle Scholar
  122. 122.
    Pryor PR, Jackson L, Gray SR, Edeling MA, Thompson A, Sanderson CM, Evans PR, Owen DJ, Paul Luzio J (2008) Molecular basis for the sorting of the SNARE VAMP7 into endocytic clathrin-coated vesicles by the arfgap hrb. Cell 134(5):817–827PubMedCrossRefGoogle Scholar
  123. 123.
    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(2):233–244PubMedCrossRefGoogle Scholar
  124. 124.
    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(5):1111–1120PubMedCrossRefGoogle Scholar
  125. 125.
    Voglmaier SM, Kam K, Yang H, Fortin DL, Hua Z, Nicoll RA, Edwards RH (2006) Distinct endocytic pathways control the rate and extent of synaptic vesicle protein recycling. Neuron 51(1):71–84PubMedCrossRefGoogle Scholar
  126. 126.
    Magalhaes AC, Dunn H, Ferguson SSG (2012) Regulation of GPCR activity, trafficking and localization by gpcr-interacting proteins. Br J Pharmacol 165(6):1717–1736PubMedCrossRefGoogle Scholar
  127. 127.
    Benovic JL, Strasser RH, Caron MG, Lefkowitz RJ (1986) Beta-adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor. Proc Natl Acad Sci U S A 83(9):2797–2801PubMedCrossRefGoogle Scholar
  128. 128.
    Fredericks ZL, Pitcher JA, Lefkowitz RJ (1996) Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor. J Biol Chem 271(23):13796–13803PubMedCrossRefGoogle Scholar
  129. 129.
    Ferguson SS, Downey WE III, Colapietro AM, Barak LS, Ménard L, Caron MG (1996) Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science 271(5247):363–366PubMedCrossRefGoogle Scholar
  130. 130.
    Goodman OB Jr, Krupnick JG, Santini F, Gurevich VV, Penn RB, Gagnon AW, Keen JH, Benovic JL (1996) Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2-­adrenergic receptor. Nature 383(6599):447–450PubMedCrossRefGoogle Scholar
  131. 131.
    Kang DS, Kern RC, Puthenveedu MA, von Zastrow M, Williams JC, Benovic JL (2009) Structure of an arrestin2-clathrin complex reveals a novel clathrin binding domain that modulates receptor trafficking. J Biol Chem 284(43):29860–29872PubMedCrossRefGoogle Scholar
  132. 132.
    Krupnick JG, Goodman OB Jr, Keen JH, Benovic JL (1997) Arrestin/clathrin interaction. Localization of the clathrin binding domain of nonvisual arrestins to the carboxy terminus. J Biol Chem 272(23):15011–15016PubMedCrossRefGoogle Scholar
  133. 133.
    Milano SK, Pace HC, Kim Y-M, Brenner C, Benovic JL (2002) Scaffolding functions of arrestin-2 revealed by crystal structure and mutagenesis. Biochemistry 41(10):3321–3328PubMedCrossRefGoogle Scholar
  134. 134.
    Laporte SA, Oakley RH, Holt JA, Barak LS, Caron MG (2000) The interaction of beta-­arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits. J Biol Chem 275(30):23120–23126PubMedCrossRefGoogle Scholar
  135. 135.
    Laporte SA, Oakley RH, Zhang J, Holt JA, Ferguson SS, Caron MG, Barak LS (1999) The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci U S A 96(7):3712–3717PubMedCrossRefGoogle Scholar
  136. 136.
    Hirsch JA, Schubert C, Gurevich VV, Sigler PB (1999) The 2.8 A crystal structure of visual arrestin: a model for arrestin’s regulation. Cell 97(2):257–269PubMedCrossRefGoogle Scholar
  137. 137.
    Gurevich VV, Gurevich EV (2004) The molecular acrobatics of arrestin activation. Trends Pharmacol Sci 25(2):105–111PubMedCrossRefGoogle Scholar
  138. 138.
    Gaidarov I, Krupnick JG, Falck JR, Benovic JL, Keen JH (1999) Arrestin function in G protein-­coupled receptor endocytosis requires phosphoinositide binding. EMBO J 18(4):871–881PubMedCrossRefGoogle Scholar
  139. 139.
    Lin FT, Krueger KM, Kendall HE, Daaka Y, Fredericks ZL, Pitcher JA, Lefkowitz RJ (1997) Clathrin-mediated endocytosis of the beta-adrenergic receptor is regulated by phosphorylation/dephosphorylation of beta-arrestin1. J Biol Chem 272(49):31051–31057PubMedCrossRefGoogle Scholar
  140. 140.
    Ahmed MR, Zhan X, Song X, Kook S, Gurevich VV, Gurevich EV (2011) Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination. Biochemistry 50(18):3749–3763PubMedCrossRefGoogle Scholar
  141. 141.
    Shenoy SK, McDonald PH, Kohout TA, Lefkowitz RJ (2001) Regulation of receptor fate by ubiquitination of activated beta 2- adrenergic receptor and beta-arrestin. Science 294(5545):1307–1313PubMedCrossRefGoogle Scholar
  142. 142.
    Chen W, Kirkbride KC, How T, Nelson CD, Mo J, Frederick JP, Wang XF, Lefkowitz RJ, Blobe GC (2003) Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science 301(5638):1394–1397PubMedCrossRefGoogle Scholar
  143. 143.
    Lin CH, MacGurn JA, Chu T, Stefan CJ, Emr SD (2008) Arrestin-related ubiquitin-ligase adaptors regulate endocytosis and protein turnover at the cell surface—supplemental info. Cell 135(4):714–725PubMedCrossRefGoogle Scholar
  144. 144.
    Yu A, Rual J-F, Tamai K, Harada Y, Vidal M, He X, Kirchhausen T (2007) Association of dishevelled with the clathrin AP-2 adaptor is required for frizzled endocytosis and planar cell polarity signaling. Dev Cell 12(1):129–141PubMedCrossRefGoogle Scholar
  145. 145.
    Canals M, Scholten DJ, de Munnik S, Han MK, Smit MJ, Leurs R (2012) Ubiquitination of CXCR7 controls receptor trafficking. PLoS One 7(3):e34192PubMedCrossRefGoogle Scholar
  146. 146.
    Wolfe BL, Marchese A, Trejo JA (2007) Ubiquitination differentially regulates clathrin-­dependent internalization of protease-activated receptor-1. J Cell Biol 177(5):905–916PubMedCrossRefGoogle Scholar
  147. 147.
    Miranda M, Sorkin A (2007) Regulation of receptors and transporters by ubiquitination: new insights into surprisingly similar mechanisms. Mol Interv 7(3):157–167PubMedCrossRefGoogle Scholar
  148. 148.
    Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229PubMedCrossRefGoogle Scholar
  149. 149.
    Polo S, Sigismund S, Faretta M, Guidi M, Capua MR, Bossi G, Chen H, De Camilli P, Di Fiore PP (2002) A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416(6879):451–455PubMedCrossRefGoogle Scholar
  150. 150.
    Sato Y, Yoshikawa A, Mimura H, Yamashita M, Yamagata A, Fukai S (2009) Structural basis for specific recognition of lys 63-linked polyubiquitin chains by tandem UIMs of RAP80. EMBO J 28(16):2461–2468PubMedCrossRefGoogle Scholar
  151. 151.
    Sims JJ, Cohen RE (2009) Linkage-specific avidity defines the lysine 63-linked polyubiquitin-­binding preference of rap80. Mol Cell 33(6):775–783PubMedCrossRefGoogle Scholar
  152. 152.
    Drake MT, Downs MA, Traub LM (2000) Epsin binds to clathrin by associating directly with the clathrin-terminal domain. Evidence for cooperative binding through two discrete sites. J Biol Chem 275(9):6479–6489PubMedCrossRefGoogle Scholar
  153. 153.
    Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12(8):553–563PubMedCrossRefGoogle Scholar
  154. 154.
    Ferguson KM, Berger MB, Mendrola JM, Cho HS, Leahy DJ, Lemmon MA (2003) EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell 11(2):507–517PubMedCrossRefGoogle Scholar
  155. 155.
    Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134PubMedCrossRefGoogle Scholar
  156. 156.
    Jiang X, Huang F, Marusyk A, Sorkin A (2003) Grb2 regulates internalization of EGF receptors through clathrin-coated pits. Mol Biol Cell 14(3):858–870PubMedCrossRefGoogle Scholar
  157. 157.
    Jiang X, Sorkin A (2003) Epidermal growth factor receptor internalization through clathrin-­coated pits requires cbl RING finger and proline-rich domains but not receptor polyubiquitylation. Traffic 4(8):529–543PubMedCrossRefGoogle Scholar
  158. 158.
    Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon WY, Beguinot L, Geiger B, Yarden Y (1998) C-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev 12(23):3663–3674PubMedCrossRefGoogle Scholar
  159. 159.
    Waterman H, Katz M, Rubin C, Shtiegman K, Lavi S, Elson A, Jovin T, Yarden Y (2002) A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. EMBO J 21(3):303–313PubMedCrossRefGoogle Scholar
  160. 160.
    Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A (2006) Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell 21(6):737–748PubMedCrossRefGoogle Scholar
  161. 161.
    Umebayashi K, Stenmark H, Yoshimori T (2008) Ubc4/5 and C-cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation. Mol Biol Cell 19(8):3454–3462PubMedCrossRefGoogle Scholar
  162. 162.
    Huang F, Goh LK, Sorkin A (2007) EGF receptor ubiquitination is not necessary for its internalization. Proc Natl Acad Sci U S A 104(43):16904–16909PubMedCrossRefGoogle Scholar
  163. 163.
    Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore PP, Dikic I (2003) Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 5(5):461–466PubMedCrossRefGoogle Scholar
  164. 164.
    Frosi Y, Anastasi S, Ballarò C, Varsano G, Castellani L, Maspero E, Polo S, Alemà S, Segatto O (2010) A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation. J Cell Biol 189(3):557–571PubMedCrossRefGoogle Scholar
  165. 165.
    Liu NS, Loo LS, Loh E, Seet L-F, Hong W (2009) Participation of Tom1L1 in EGF-stimulated endocytosis of EGF receptor. EMBO J 28(22):3485–3499PubMedCrossRefGoogle Scholar
  166. 166.
    Madshus IH, Stang E (2009) Internalization and intracellular sorting of the EGF receptor: a model for understanding the mechanisms of receptor trafficking. J Cell Sci 122(pt 19):3433–3439PubMedCrossRefGoogle Scholar
  167. 167.
    Sorkin A, Goh LK (2009) Endocytosis and intracellular trafficking of erbbs. Exp Cell Res 315(4):683–696PubMedCrossRefGoogle Scholar
  168. 168.
    Duval M, Bédard-Goulet S, Delisle C, Gratton J-P (2003) Vascular endothelial growth factor-­dependent down-regulation of flk-1/KDR involves cbl-mediated ubiquitination. Consequences on nitric oxide production from endothelial cells. J Biol Chem 278(22):20091–20097PubMedCrossRefGoogle Scholar
  169. 169.
    Fasen K, Cerretti DP, Huynh-Do U (2008) Ligand binding induces Cbl-dependent EphB1 receptor degradation through the lysosomal pathway. Traffic 9(2):251–266PubMedCrossRefGoogle Scholar
  170. 170.
    Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S et al (1999) Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 4(6):1029–1040PubMedCrossRefGoogle Scholar
  171. 171.
    Marmor MD, Yarden Y (2004) Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene 23(11):2057–2070PubMedCrossRefGoogle Scholar
  172. 172.
    Miyake S, Mullane-Robinson KP, Lill NL, Douillard P, Band H (1999) Cbl-mediated negative regulation of platelet-derived growth factor receptor-dependent cell proliferation. A critical role for cbl tyrosine kinase-binding domain. J Biol Chem 274(23):16619–16628PubMedCrossRefGoogle Scholar
  173. 173.
    Penengo L, Rubin C, Yarden Y, Gaudino G (2003) C-Cbl is a critical modulator of the Ron tyrosine kinase receptor. Oncogene 22(24):3669–3679PubMedCrossRefGoogle Scholar
  174. 174.
    Wilhelmsen K, Burkhalter S, van der Geer P (2002) C-Cbl binds the CSF-1 receptor at tyrosine 973, a novel phosphorylation site in the receptor’s carboxy-terminus. Oncogene 21(7):1079–1089PubMedCrossRefGoogle Scholar
  175. 175.
    Arévalo JC, Waite J, Rajagopal R, Beyna M, Chen Z-Y, Lee FS, Chao MV (2006) Cell survival through trk neurotrophin receptors is differentially regulated by ubiquitination. Neuron 50(4):549–559PubMedCrossRefGoogle Scholar
  176. 176.
    Monami G, Emiliozzi V, Morrione A (2008) Grb10/Nedd4-mediated multiubiquitination of the insulin-like growth factor receptor regulates receptor internalization. J Cell Physiol 216(2):426–437PubMedCrossRefGoogle Scholar
  177. 177.
    Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, Rotin D (2011) Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function. EMBO J 30(16):3259–3273PubMedCrossRefGoogle Scholar
  178. 178.
    Sundvall M, Korhonen A, Paatero I, Gaudio E, Melino G, Croce CM, Aqeilan RI, Elenius K (2008) Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms. Proc Natl Acad Sci U S A 105(11):4162–4167PubMedCrossRefGoogle Scholar
  179. 179.
    Vecchione A, Marchese A, Henry P, Rotin D, Morrione A (2003) The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol 23(9):3363–3372PubMedCrossRefGoogle Scholar
  180. 180.
    Rotin D, Staub O (2012) Nedd4-2 and the regulation of epithelial sodium transport. Front Physiol 3:212PubMedCrossRefGoogle Scholar
  181. 181.
    Butterworth MB (2010) Regulation of the epithelial sodium channel (ENaC) by membrane trafficking. Biochim Biophys Acta 1802(12):1166–1177PubMedCrossRefGoogle Scholar
  182. 182.
    Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D (1997) Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J 16(21):6325–6336PubMedCrossRefGoogle Scholar
  183. 183.
    Miranda M, Wu CC, Sorkina T, Korstjens DR, Sorkin A (2005) Enhanced ubiquitylation and accelerated degradation of the dopamine transporter mediated by protein kinase C. J Biol Chem 280(42):35617–35624PubMedCrossRefGoogle Scholar
  184. 184.
    García-Tardón N, González-González IM, Martínez-Villarreal J, Fernández-Sánchez E, Giménez C, Zafra F (2012) Protein kinase C (PKC)-promoted endocytosis of glutamate transporter GLT-1 requires ubiquitin ligase nedd4-2-dependent ubiquitination but not phosphorylation. J Biol Chem 287(23):19177–19187PubMedCrossRefGoogle Scholar
  185. 185.
    Fernández-Sánchez E, Martínez-Villarreal J, Giménez C, Zafra F (2009) Constitutive and regulated endocytosis of the glycine transporter GLYT1b is controlled by ubiquitination. J Biol Chem 284(29):19482–19492PubMedCrossRefGoogle Scholar
  186. 186.
    de Juan-Sanz J, Zafra F, López-Corcuera B, Aragón C (2011) Endocytosis of the neuronal glycine transporter GLYT2: role of membrane rafts and protein kinase c-dependent ubiquitination. Traffic 12(12):1850–1867PubMedCrossRefGoogle Scholar
  187. 187.
    Vina-Vilaseca A, Bender-Sigel J, Sorkina T, Closs EI, Sorkin A (2011) Protein kinase c-dependent ubiquitination and clathrin-mediated endocytosis of the cationic amino acid transporter CAT-1. J Biol Chem 286(10):8697–8706PubMedCrossRefGoogle Scholar
  188. 188.
    Loerke D, Mettlen M, Yarar D, Jaqaman K, Jaqaman H, Danuser G, Schmid SL (2009) Cargo and dynamin regulate clathrin-coated pit maturation. PLoS Biol 7(3):e57PubMedCrossRefGoogle Scholar
  189. 189.
    Mettlen M, Loerke D, Yarar D, Danuser G, Schmid SL (2010) Cargo- and adaptor-specific mechanisms regulate clathrin-mediated endocytosis. J Cell Biol 188(6):919–933PubMedCrossRefGoogle Scholar
  190. 190.
    Johannessen LE, Pedersen NM, Pedersen KW, Madshus IH, Stang E (2006) Activation of the epidermal growth factor (EGF) receptor induces formation of EGF receptor- and grb2-­containing clathrin-coated pits. Mol Cell Biol 26(2):389–401PubMedCrossRefGoogle Scholar
  191. 191.
    Puri C, Tosoni D, Comai R, Rabellino A, Segat D, Caneva F, Luzzi P, Di Fiore PP, Tacchetti C (2005) Relationships between EGFR signaling-competent and endocytosis-competent membrane microdomains. Mol Biol Cell 16(6):2704–2718PubMedCrossRefGoogle Scholar
  192. 192.
    Rappoport JZ, Simon SM (2009) Endocytic trafficking of activated EGFR is AP-2 dependent and occurs through preformed clathrin spots. J Cell Sci 122(pt 9):1301–1305PubMedCrossRefGoogle Scholar
  193. 193.
    Santini F, Gaidarov I, Keen JH (2002) G protein-coupled receptor/arrestin3 modulation of the endocytic machinery. J Cell Biol 156(4):665–676PubMedCrossRefGoogle Scholar
  194. 194.
    Cureton DK, Massol RH, Saffarian S, Kirchhausen TL, Whelan SP (2009) Vesicular stomatitis virus enters cells through vesicles incompletely coated with clathrin that depend upon actin for internalization. PLoS Pathog 5(4):e1000394PubMedCrossRefGoogle Scholar
  195. 195.
    Liu AP, Aguet F, Danuser G, Schmid SL (2010) Local clustering of transferrin receptors promotes clathrin-coated pit initiation. J Cell Biol 191(7):1381–1393PubMedCrossRefGoogle Scholar
  196. 196.
    Meyerholz A, Hinrichsen L, Groos S, Esk PC, Brandes G, Ungewickell EJ (2005) Effect of clathrin assembly lymphoid myeloid leukemia protein depletion on clathrin coat formation. Traffic 6(12):1225–1234PubMedCrossRefGoogle Scholar
  197. 197.
    Morgan JR, Zhao X, Womack M, Prasad K, Augustine GJ, Lafer EM (1999) A role for the clathrin assembly domain of AP180 in synaptic vesicle endocytosis. J Neurosci 19(23):10201–10212PubMedGoogle Scholar
  198. 198.
    Nonet ML, Holgado AM, Brewer F, Serpe CJ, Norbeck BA, Holleran J, Wei L, Hartwieg E, Jorgensen EM, Alfonso A (1999) UNC-11, a Caenorhabditis elegans AP180 homologue, regulates the size and protein composition of synaptic vesicles. Mol Biol Cell 10(7): 2343–2360PubMedGoogle Scholar
  199. 199.
    Heuser J, Kirchhausen T (1985) Deep-etch views of clathrin assemblies. J Ultrastruct Res 92(1–2):1–27PubMedCrossRefGoogle Scholar
  200. 200.
    Saffarian S, Cocucci E, Kirchhausen T (2009) Distinct dynamics of endocytic clathrin-coated pits and coated plaques. PLoS Biol 7(9):e1000191PubMedCrossRefGoogle Scholar
  201. 201.
    Puthenveedu MA, von Zastrow M (2006) Cargo regulates clathrin-coated pit dynamics. Cell 127(1):113–124PubMedCrossRefGoogle Scholar
  202. 202.
    Ritter SL, Hall RA (2009) Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol 10(12):819–830PubMedCrossRefGoogle Scholar
  203. 203.
    Tosoni D, Puri C, Confalonieri S, Salcini AE, De Camilli P, Tacchetti C, Di Fiore PP (2005) TTP specifically regulates the internalization of the transferrin receptor. Cell 123(5):875–888PubMedCrossRefGoogle Scholar
  204. 204.
    Warren RA, Green FA, Enns CA (1997) Saturation of the endocytic pathway for the transferrin receptor does not affect the endocytosis of the epidermal growth factor receptor. J Biol Chem 272(4):2116–2121PubMedCrossRefGoogle Scholar
  205. 205.
    Warren RA, Green FA, Stenberg PE, Enns CA (1998) Distinct saturable pathways for the endocytosis of different tyrosine motifs. J Biol Chem 273(27):17056–17063PubMedCrossRefGoogle Scholar
  206. 206.
    Marks MS, Woodruff L, Ohno H, Bonifacino JS (1996) Protein targeting by tyrosine- and di-leucine-based signals: evidence for distinct saturable components. J Cell Biol 135(2):341–354PubMedCrossRefGoogle Scholar
  207. 207.
    Cao TT, Mays RW, von Zastrow M (1998) Regulated endocytosis of G protein-coupled receptors by a biochemically and functionally distinct subpopulation of clathrin-coated pits. J Biol Chem 273(38):24592–24602PubMedCrossRefGoogle Scholar
  208. 208.
    Mundell SJ, Luo J, Benovic JL, Conley PB, Poole AW (2006) Distinct clathrin-coated pits sort different G protein-coupled receptor cargo. Traffic 7(10):1420–1431PubMedCrossRefGoogle Scholar
  209. 209.
    Lakadamyali M, Rust MJ, Zhuang X (2006) Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes. Cell 124(5):997–1009PubMedCrossRefGoogle Scholar
  210. 210.
    Leonard D, Hayakawa A, Lawe D, Lambright D, Bellve KD, Standley C, Lifshitz LM, Fogarty KE, Corvera S (2008) Sorting of EGF and transferrin at the plasma membrane and by cargo-specific signaling to eea1-enriched endosomes. J Cell Sci 121(pt 20):3445–3458PubMedCrossRefGoogle Scholar
  211. 211.
    Doyon JB, Zeitler B, Cheng J, Cheng AT, Cherone JM, Santiago Y, Lee AH et al (2011) Rapid and efficient clathrin-mediated endocytosis revealed in genome-edited mammalian cells. Nat Cell Biol 13(3):331–337PubMedCrossRefGoogle Scholar
  212. 212.
    Eliceiri KW, Berthold MR, Goldberg IG, Ibáñez L, Manjunath BS, Martone ME, Murphy RF et al (2012) Biological imaging software tools. Nat Methods 9(7):697–710PubMedCrossRefGoogle Scholar
  213. 213.
    Jaqaman K, Loerke D, Mettlen M, Kuwata H, Grinstein S, Schmid SL, Danuser G (2008) Robust single-particle tracking in live-cell time-lapse sequences. Nat Methods 5(8): 695–702PubMedCrossRefGoogle Scholar
  214. 214.
    Liang L, Shen H, De Camilli P, Duncan JS (2010) Tracking clathrin coated pits with a multiple hypothesis based method. Med Image Comput Comput Assist Interv 13(pt 2):315–322PubMedGoogle Scholar
  215. 215.
    Meijering E, Dzyubachyk O, Smal I (2012) Methods for cell and particle tracking. Methods Enzymol 504:183–200PubMedCrossRefGoogle Scholar
  216. 216.
    Weigert R, Sramkova M, Parente L, Amornphimoltham P, Masedunskas A (2010) Intravital microscopy: a novel tool to study cell biology in living animals. Histochem Cell Biol 133(5):481–491PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cell BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Department of Biological SciencesCarnegie Mellon UniversityPittsburghUSA

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