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EH proteins

Multivalent regulators of endocytosis (and other pathways)

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Abstract

Endocytosis is a protein and lipid-trafficking pathway that occurs in all eukaryotic cells. It involves the internalization of plasma membrane proteins and lipids into the cell and the subsequent degradation of proteins in the lysosome or the recycling of proteins and lipids back to the plasma membrane. Over the past decade, studies in yeast and mammalian cells have revealed endocytosis to be a very complex molecular process that depends on regulated interactions between a variety of proteins and lipids. The Eps15 homology (EH) domain is a conserved, modular protein-interaction domain found in several endocytosis proteins. EH proteins can function as key regulators of endocytosis through their ability to interact with many of the other proteins involved in this process.

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References

  1. Mellman, I. (1996) Endocytosis and molecular sorting. Annu. Rev. Cell. Dev. Biol. 12, 575–625.

    PubMed  CAS  Google Scholar 

  2. Buckley, K. M., et al. (2000) Regulation of neuronal function by protein trafficking: a role for the endosomal pathway. J. Physiol. 525, 11–19.

    PubMed  CAS  Google Scholar 

  3. Mansour, M. K. and Levitz, S. M. (2002) Interactions of fungi with phagocytes. Curr. Opin. Microbiol. 5, 359–365.

    PubMed  CAS  Google Scholar 

  4. Lanzavecchia, A. (1996) Mechanisms of antigen uptake for presentation. Curr. Opin. Immunol. 8, 348–54.

    PubMed  CAS  Google Scholar 

  5. Floyd, S. and De Camilli, P. (1998) Endocytosis proteins and cancer: a potential link? Trends Cell. Biol. 8, 299–301.

    PubMed  CAS  Google Scholar 

  6. Pawson, T. (1995) Protein-tyrosine kinases. Getting down to specifics. Nature 373, 477–478.

    PubMed  CAS  Google Scholar 

  7. Roth, T. F. and Porter, K. R. (1964) Yolk protein uptake in the oocyte of the mosquito Aedes Aegypti L. J. Cell. Biol. 20, 313–332.

    PubMed  CAS  Google Scholar 

  8. Pearse, B. M. (1976) Clathrin: a unique protein associated with intracellular transfer of membrane by coated vesicles. Proc. Natl. Acad. Sci. U. S. A. 73, 1255–1259.

    PubMed  CAS  Google Scholar 

  9. Ungewickell, E. and Branton, D. (1981) Assembly units of clathrin coats. Nature 289, 420–422.

    PubMed  CAS  Google Scholar 

  10. Crowther, R. A. and Pearse, B. M. (1981) Assembly and packing of clathrin into coats. J. Cell. Biol. 91, 790–797.

    PubMed  CAS  Google Scholar 

  11. Keen, J. H., Willingham, M. C. and Pastan, I. H. (1979) Clathrin-coated vesicles: isolation, dissociation and factor-dependent reassociation of clathrin baskets. Cell 16, 303–312.

    PubMed  CAS  Google Scholar 

  12. Zaremba, S. and Keen, J. H. (1983) Assembly polypeptides from coated vesicles mediate reassembly of unique clathrin coats. J. Cell. Biol. 97, 1339–1347.

    PubMed  CAS  Google Scholar 

  13. Robinson, M. S. and Pearse, B. M. (1986) Immunofluorescent localization of 100K coated vesicle proteins. J. Cell. Biol. 102, 48–54.

    PubMed  CAS  Google Scholar 

  14. Robinson, M. S. and Bonifacino, J. S. (2001) Adaptor-related proteins. Curr. Opin. Cell. Biol. 13, 444–453.

    PubMed  CAS  Google Scholar 

  15. Collins, B. M., et al. (2002) Molecular architecture and functional model of the endocytic AP2 complex. Cell 109, 523–535.

    PubMed  CAS  Google Scholar 

  16. Hirst, J. and Robinson, M. S. (1998) Clathrin and adaptors. Biochim. Biophys. Acta 1404, 173–193.

    PubMed  CAS  Google Scholar 

  17. McNiven, M. A. (1998) Dynamin: a molecular motor with pinchase action. Cell 94, 151–154.

    PubMed  CAS  Google Scholar 

  18. Song, B. D. and Schmid, S. L. (2003) A molecular motor or a regulator? Dynamin's in a class of its own. Biochemistry 42, 1369–1376.

    PubMed  CAS  Google Scholar 

  19. Munn, A. L. (2001) Molecular requirements for the internalisation step of endocytosis: insights from yeast. Biochim. Biophys. Acta 1535, 236–257.

    PubMed  CAS  Google Scholar 

  20. Marsh, M. and McMahon, H. T. (1999) The structural era of endocytosis. Science 285, 215–220.

    PubMed  CAS  Google Scholar 

  21. Evans, P. R. and Owen, D. J. (2002) Endocytosis and vesicle trafficking. Curr. Opin. Struct. Biol. 12, 814–821.

    PubMed  CAS  Google Scholar 

  22. Schafer, D. A. (2002) Coupling actin dynamics and membrane dynamics during endocytosis. Curr. Opin. Cell. Biol. 14, 76–81.

    PubMed  CAS  Google Scholar 

  23. Hicke, L. (2001) A new ticket for entry into budding vesicles-ubiquitin. Cell 106, 527–530.

    PubMed  CAS  Google Scholar 

  24. D'Hondt, K., Heese-Peck, A., and Riezman, H. (2000) Protein and lipid requirements for endocytosis. Annu. Rev. Genet. 34, 255–295.

    PubMed  Google Scholar 

  25. Wong, W. T., et al. (1995) A protein-binding domain, EH, identified in the receptor tyrosine kinase substrate Eps15 and conserved in evolution. Proc. Natl. Acad. Sci. U. S. A. 92, 9530–9534.

    PubMed  CAS  Google Scholar 

  26. Confalonieri, S. and Di Fiore, P. P. (2002) The Eps15 homology (EH) domain. FEBS Lett. 513, 24–29.

    PubMed  CAS  Google Scholar 

  27. Santolini, E., et al. (1999) The EH network. Exp. Cell Res. 253, 186–209.

    PubMed  CAS  Google Scholar 

  28. Fazioli, F., et al. (1993) eps15, a novel tyrosine kinase substrate, exhibits transforming activity. Mol. Cell. Biol. 9, 5814–5828.

    Google Scholar 

  29. Paoluzi, S., et al. (1998) Recognition specificity of individual EH domains of mammals and yeast. EMBO J. 17, 6541–6550.

    PubMed  CAS  Google Scholar 

  30. Lewit-Bentley, A. and Rety, S. (2000) EF-hand calcium-binding proteins. Curr. Opin. Struct. Biol. 10, 637–643.

    PubMed  CAS  Google Scholar 

  31. Yamabhai, M., et al. (1998) Intersectin, a novel adaptor protein with two Eps15 homology and five Src homology 3 domains. J. Biol. Chem. 273, 31401–31407.

    PubMed  CAS  Google Scholar 

  32. Mintz, L., et al. (1999) EHD1—an EH-domain-containing protein with a specific expression pattern. Genomics 59, 66–76.

    PubMed  CAS  Google Scholar 

  33. Yamaguchi, A., et al. (1997) An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1. J. Biol. Chem. 272, 31230–31234.

    PubMed  CAS  Google Scholar 

  34. Pohl, U., et al. (2000) EHD2, EHD3, and EHD4 encode novel members of a highly conserved family of EH domain-containing proteins. Genomics 63, 255–262.

    PubMed  CAS  Google Scholar 

  35. Ikeda, M., et al. (1998) Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral. J. Biol. Chem. 273, 814–821.

    PubMed  CAS  Google Scholar 

  36. Carbone, R., et al. (1997) eps15 and eps15R are essential components of the endocytic pathway. Cancer Res. 57, 5498–5504.

    PubMed  CAS  Google Scholar 

  37. Hofmann, K. and Falquet, L. (2001) A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends Biochem. Sci. 26, 347–350.

    PubMed  CAS  Google Scholar 

  38. Di Fiore, P. P., Polo, S. and Hofmann, K. (2003) When ubiquitin meets ubiquitin receptors: a signalling connection. Nat Rev Mol. Cell. Biol. 4, 491–497.

    PubMed  Google Scholar 

  39. Polo, S., et al. (2003) EH and UIM: endocytosis and more. Sci. STKE 213, 17.

    Google Scholar 

  40. Klapisz, E., et al. (2002) A ubiquitin-interacting motif (UIM) is essential for Eps15 and Eps15R ubiquitination. J. Biol. Chem. 277, 30746–30753.

    PubMed  CAS  Google Scholar 

  41. van Delft, S., et al. (1997) Epidermal growth factor induces ubiquitination of Eps15. J. Biol. Chem. 272, 14013–10416.

    PubMed  Google Scholar 

  42. Polo, S., et al. (2002) A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451–455.

    PubMed  CAS  Google Scholar 

  43. Salcini, A. E., et al. (2001) The Eps15 C. elegans homologue EHS-1 is implicated in synaptic vesicle recycling. Nat. Cell. Biol. 3, 755–760.

    PubMed  CAS  Google Scholar 

  44. Hussain, N. K., et al. (1999) Splice variants of intersectin are components of the endocytic machinery in neurons and nonneuronal cells. J. Biol. Chem. 274, 15671–15677.

    PubMed  CAS  Google Scholar 

  45. Hussain, N. K., et al. (2001) Endocytic protein intersectin-1 regulates actin assembly via Cdc42 and N-WASP. Nat. Cell. Biol. 3, 927–932.

    PubMed  CAS  Google Scholar 

  46. Machesky, L. M. and Insall, R. H. (1998) Scar1 and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr. Biol. 8, 25, 1347–1356.

    PubMed  CAS  Google Scholar 

  47. Sengar, A. S., et al. (1999) The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15. EMBO J. 18, 1159–1171.

    PubMed  CAS  Google Scholar 

  48. Roos, J. and Kelly, R. B. (1998) Dap160, a neural-specific Eps15 homology and multiple SH3 domain-containing protein that interacts with Drosophila dynamin. J. Biol. Chem. 273, 19108–19119.

    PubMed  CAS  Google Scholar 

  49. Simpson, F., et al. (1999) SH3-domain-containing proteins function at distinct steps in clathrin-coated vesicle formation. Nat. Cell. Biol 1, 119–124.

    PubMed  CAS  Google Scholar 

  50. Caplan, S., et al. (2002) A tubular EHD1-containing compartment involved in the recycling of major histocompatibility complex class I molecules to the plasma membrane. EMBO J. 21, 2557–2567.

    PubMed  CAS  Google Scholar 

  51. Galperin, E., et al. (2002) EHD3: a protein that resides in recycling tubular and vesicular membrane structures and interacts with EHD1. Traffic 3, 575–589.

    PubMed  CAS  Google Scholar 

  52. Grant, B., et al. (2001) Evidence that RME-1, a conserved C. elegans EH-domain protein, functions in endocytic recycling. Nat. Cell. Biol. 3, 573–579.

    PubMed  CAS  Google Scholar 

  53. Lin, S. X., et al. (2001) Rme-1 regulates the distribution and function of the endocytic recycling compartment in mammalian cells. Nat. Cell Biol. 3, 567–572.

    PubMed  CAS  Google Scholar 

  54. Cullis, D. N., et al. (2002) Rab11-FIP2, an adaptor protein connecting cellular components involved in internalization and recycling of epidermal growth factor receptors. J. Biol. Chem. 277, 49158–49166.

    PubMed  CAS  Google Scholar 

  55. Morinaka, K., et al. (1999) Epsin binds to the EH domain of POB1 and regulates receptor-mediated endocytosis. Oncogene 18, 5915–5922.

    PubMed  CAS  Google Scholar 

  56. Kariya, K., et al. (2000) Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation. J. Biol. Chem. 275, 18399–18406.

    PubMed  CAS  Google Scholar 

  57. Pearse, B. M. and Robinson, M. S. (1990) Clathrin, adaptors, and sorting. Annu. Rev. Cell. Biol. 6, 151–171.

    PubMed  CAS  Google Scholar 

  58. Page, L. J., et al. (1999) Gamma-synergin: an EH domain-containing protein that interacts with gamma-adaptin. J. Cell. Biol. 146, 993–1004.

    PubMed  CAS  Google Scholar 

  59. Shaw, J. D., et al. (2001) Yeast as a model system for studying endocytosis. Exp. Cell Res. 271, 1–9.

    PubMed  CAS  Google Scholar 

  60. Geli, M. I. and Riezman, H. (1998) Endocytic internalization in yeast and animal cells: similar and different. J. Cell. Sci. 111, 1031–1037.

    PubMed  CAS  Google Scholar 

  61. Baggett, J. J. and Wendland, B. (2001) Clathrin function in yeast endocytosis. Traffic 2, 297–302.

    PubMed  CAS  Google Scholar 

  62. Raths, S., et al. (1993) end3 and end4: two mutants defective in receptor-mediated and fluid-phase endocytosis in Saccharomyces cerevisiae. J. Cell. Biol. 120, 55–65.

    PubMed  CAS  Google Scholar 

  63. Benedetti, H., et al. (1994) The END3 gene encodes a protein that is required for the internalization step of endocytosis and for actin cytoskeleton organization in yeast. Mol. Biol. Cell. 5, 1023–1037.

    PubMed  CAS  Google Scholar 

  64. Sachs, A. B. and Deardorff, J. A. (1992) Translation initiation requires the PAB-dependent poly(A) ribonuclease in yeast. Cell 70, 961–973.

    PubMed  CAS  Google Scholar 

  65. Wendland, B., et al. (1996) A novel fluorescence-activated cell sorter-based screen for yeast endocytosis mutants identifies a yeast homologue of mammalian eps15. J. Cell. Biol. 135, 1485–1500.

    PubMed  CAS  Google Scholar 

  66. Duncan, M. C., et al. (2001) Yeast Eps15-like endocytic protein, Pan1p, activates the Arp2/3 complex. Nat. Cell. Biol. 3, 687–690.

    PubMed  CAS  Google Scholar 

  67. Wendland, B. and Emr, S. D. (1998) Pan1p, yeast eps15, functions as a multivalent adaptor that coordinates protein-protein interactions essential for endocytosis. J. Cell. Biol. 141, 71–84.

    PubMed  CAS  Google Scholar 

  68. Tang, H. Y. and Cai, M. (1996) The EH-domain-containing protein Pan1 is required for normal organization of the actin cytoskeleton in Saccharomyces cerevisiae. Mol. Cell. Biol. 16, 4897–4914.

    PubMed  CAS  Google Scholar 

  69. Gagny, B., et al. (2000) A novel EH domain protein of Saccharomyces cerevisiae, Ede1p, involved in endocytosis. J. Cell. Sci. 113 3309–3319.

    PubMed  CAS  Google Scholar 

  70. Mueller, T. D. and Feigon, J. (2002) Solution structures of UBA domains reveal a conserved hydrophobic surface for protein-protein interactions. J. Mol. Biol. 319, 1243–1255.

    PubMed  CAS  Google Scholar 

  71. Schnell, J. D. and Hicke, L. (2003) Non-traditional functions of ubiquitin and ubiquitin-binding proteins. J. Biol. Chem. 278, 35857–35860.

    PubMed  CAS  Google Scholar 

  72. Mueller, T. D., Kamionka, M., and Feigon, J. (2004) Specificity of the interaction between UBA domains and ubiquitin. J. Biol. Chem. 279, 11926–11936.

    PubMed  CAS  Google Scholar 

  73. Aguilar, R. C., Watson, H. A., and Wendland, B. (2003) The yeast Epsin Ent1 is recruited to membranes through multiple independent interactions. J. Biol. Chem. 278, 10737–10743.

    PubMed  CAS  Google Scholar 

  74. Shih, S. C., et al. (2002) Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis. Nat. Cell Biol. 4, 389–393.

    PubMed  CAS  Google Scholar 

  75. Smith, J. S., Caputo, E., and Boeke, J. D. (1999) A genetic screen for ribosomal DNA silencing defects identifies multiple DNA replication and chromatin-modulating factors. Mol. Cell. Biol. 19, 3184–3197.

    PubMed  CAS  Google Scholar 

  76. Benmerah, A., et al. (1995) The tyrosine kinase substrate eps15 is constitutively associated with the plasma membrane adaptor AP-2. J. Cell. Biol. 131, 1831–1838.

    PubMed  CAS  Google Scholar 

  77. Coda, L., et al. (1998) Eps15R is a tyrosine kinase substrate with characteristics of a docking protein possibly involved in coated pits-mediated internalization. J. Biol. Chem. 273, 3003–3012.

    PubMed  CAS  Google Scholar 

  78. Benmerah, A., et al. (1996) The ear of alpha-adaptin interacts with the COOH-terminal domain of the Eps 15 protein. J. Biol. Chem. 271, 12111–12116.

    PubMed  CAS  Google Scholar 

  79. Iannolo, G., et al. (1997) Mapping of the molecular determinants involved in the interaction between eps15 and AP-2. Cancer Res. 57, 240–245.

    PubMed  CAS  Google Scholar 

  80. Benmerah, A., et al. (1998) AP-2/Eps15 interaction is required for receptor-mediated endocytosis. J. Cell. Biol. 140, 1055–1062.

    PubMed  CAS  Google Scholar 

  81. Benmerah, A., et al. (1999) Inhibition of clathrin-coated pit assembly by an Eps15 mutant. J. Cell Sci. 112 1303–1311.

    PubMed  CAS  Google Scholar 

  82. Benmerah, A., et al. (2000) Mapping of Eps15 domains involved in its targeting to clathrin-coated pits. J. Biol. Chem. 275, 3288–3295.

    PubMed  CAS  Google Scholar 

  83. Tebar, F., et al. (1996) Eps15 is a component of clathrin-coated pits and vesicles and is located at the rim of coated pits. J. Biol. Chem. 271, 28727–28730.

    PubMed  CAS  Google Scholar 

  84. Cupers, P., Jadhav, A. P., and Kirchhausen, T. (1998) Assembly of clathrin coats disrupts the association between Eps15 and AP-2 adaptors. J. Biol. Chem. 273, 1847–1850.

    PubMed  CAS  Google Scholar 

  85. Morgan, J. R., et al. (2003) Eps15 homology domain-NPF motif interactions regulate clathrin coat assembly during synaptic vesicle recycling. J. Biol. Chem. 278, 33583–33592.

    PubMed  CAS  Google Scholar 

  86. Sorkina, T., et al. (1999) Clathrin, adaptors and eps15 in endosomes containing activated epidermal growth factor receptors. J. Cell. Sci. 112 317–327.

    PubMed  CAS  Google Scholar 

  87. Torrisi, M., et al. (1999) Eps15 is recruited to the plasma membrane upon epidermal growth factor receptor activation and localizes to components of the endocytic pathway during receptor internalization. Mol. Biol. Cell. 10, 417–434.

    PubMed  CAS  Google Scholar 

  88. Leof, E. B. (2000) Growth factor receptor signalling: location, location, location. Trends Cell. Biol. 10, 343–348.

    PubMed  CAS  Google Scholar 

  89. Whitacre, J., et al. (2001) Generation of an isogenic collection of yeast actin mutants and identification of three interrelated phenotypes. Genetics 157, 533–543.

    PubMed  CAS  Google Scholar 

  90. Ayscough, K. R. (2000) Endocytosis and the development of cell polarity in yeast require a dynamic F-actin cytoskeleton. Curr. Biol. 10, 1587–1590.

    PubMed  CAS  Google Scholar 

  91. Ayscough, K. R., et al. (1997) High rates of actin filament turnover in budding yeast and roles for actin in establishment and maintenance of cell polarity revealed using the actin inhibitor latrunculin-A. J. Cell. Biol. 137, 399–416.

    PubMed  CAS  Google Scholar 

  92. Qualmann, B., Kessels, M. M. and Kelly, R. B. (2000) Molecular links between endocytosis and the actin cytoskeleton. J. Cell. Biol. 150, F111-F116.

    PubMed  CAS  Google Scholar 

  93. Engqvist-Goldstein, A. E. and Drubin, D. G. (2003) Actin assembly and endocytosis: from yeast to mammals. Annu. Rev. Cell Dev. Biol. 19, 287–332.

    PubMed  CAS  Google Scholar 

  94. Hall, A. (1998) Rho GTPases and the actin cytoskeleton. Science 279, 509–514.

    PubMed  CAS  Google Scholar 

  95. Rohatgi, R., et al. (1999) The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97, 221–231.

    PubMed  CAS  Google Scholar 

  96. Higgs, H. N. and Pollard, T. D. (1999) Regulation of actin polymerization by Arp2/3 complex and WASp/Scar proteins. J. Biol. Chem. 274, 32531–32534.

    PubMed  CAS  Google Scholar 

  97. Merrifield, C. J., et al. (1999) Endocytic vesicles move at the tips of actin tails in cultured mast cells. Nat. Cell. Biol. 1, 72–74.

    PubMed  CAS  Google Scholar 

  98. Jenna, S., et al. (2002) The activity of the GTPase-activating protein CdGAP is regulated by the endocytic protein intersectin. J. Biol. Chem. 277, 6366–6373.

    PubMed  CAS  Google Scholar 

  99. Zhang, J. et al. (1999) Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in Wiskott-Aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190, 1329–1342.

    PubMed  CAS  Google Scholar 

  100. Pucharcos, C., Estivill, X., and de la Luna, S. (2000) Intersectin 2, a new multimodular protein involved in clathrin-mediated endocytosis. FEBS Lett. 478, 43–51.

    PubMed  CAS  Google Scholar 

  101. McGavin, M. K., et al. (2001) The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis. J. Exp. Med. 194, 1777–1787.

    PubMed  CAS  Google Scholar 

  102. Tang, H. Y., Munn, A., and Cai, M. (1997) EH domain proteins Pan1p and End3p are components of a complex that plays a dual role in organization of the cortical actin cytoskeleton and endocytosis in Saccharomyces cerevisiae. Mol. Cell. Biol. 17, 4294–4304.

    PubMed  CAS  Google Scholar 

  103. Schott, D., Huffaker, T., and Bretscher, A. (2002) Microfilaments and microtubules: the news from yeast. Curr. Opin. Microbiol. 5, 564–574.

    PubMed  CAS  Google Scholar 

  104. Wendland, B., Steece, K. E. and Emr, S. D. (1999) Yeast epsins contain an essential N-terminal ENTH domain, bind clathrin and are required for endocytosis. EMBO J. 18, 4383–4393.

    PubMed  CAS  Google Scholar 

  105. Salcini, A. E., et al. (1997) Binding specificity and in vivo targets of the EH domain, a novel protein-protein interaction module. Genes Dev. 11, 2239–2249.

    PubMed  CAS  Google Scholar 

  106. Uemura, T., et al. (1989) numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos. Cell 58, 349–360.

    PubMed  CAS  Google Scholar 

  107. Bogerd, H. P., et al. (1995) Identification of a novel cellular cofactor for the Rev/Rex class of retroviral regulatory proteins. Cell 82, 485–494.

    PubMed  CAS  Google Scholar 

  108. Fritz, C. C., Zapp, M. L. and Green, M. R. (1995) A human nucleoporin-like protein that specifically interacts with HIV Rev. Nature 376, 530–533.

    PubMed  CAS  Google Scholar 

  109. de Beer, T., et al. (2000) Molecular mechanism of NPF recognition by EH domains. Nat. Struct. Biol. 7, 1018–1022.

    PubMed  Google Scholar 

  110. Kim, S., et al. (2001) Solution structure of the Reps1 EH domain and characterization of its binding to NPF target sequences. Biochemistry 40, 6776–6685.

    PubMed  CAS  Google Scholar 

  111. de Beer, T., et al. (1998) Structure and Asn-Pro-Phe binding pocket of the Eps15 homology domain. Science 281, 1357–1360.

    PubMed  Google Scholar 

  112. Cullen, B. R. (1998) Retroviruses as model systems for the study of nuclear RNA export pathways. Virology 249, 203–210.

    PubMed  CAS  Google Scholar 

  113. Fischer, U., et al. (1995) The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 82, 475–483.

    PubMed  CAS  Google Scholar 

  114. Fridell, R. A., Bogerd, H. P. and Cullen, B. R. (1996) Nuclear export of late HIV-1 mRNAs occurs via a cellular protein export pathway. Proc. Natl. Acad. Sci. U. S. A. 93, 4421–4424.

    PubMed  CAS  Google Scholar 

  115. Fritz, C. C. and Green, M. R. (1996) HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs. Curr. Biol. 6, 848–854.

    PubMed  CAS  Google Scholar 

  116. Roth, J., et al. (1998) Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the huMan immunodeficiency virus rev protein. EMBO J. 17, 554–564.

    PubMed  CAS  Google Scholar 

  117. Doria, M., et al. (1999) The eps15 homology (EH) domain-based interaction between eps15 and hrb connects the molecular machinery of endocytosis to that of nucleocytosolic transport. J. Cell. Biol. 14, 1379–1384.

    Google Scholar 

  118. Poupon, V., et al. (2002) Differential nucleocytoplasmic trafficking between the related endocytic proteins Eps15 and Eps15R. J. Biol. Chem. 277, 8941–8948.

    PubMed  CAS  Google Scholar 

  119. Vecchi, M., et al. (2001) Nucleocytoplasmic shuttling of endocytic proteins. J. Cell. Biol. 153, 1511–1517.

    PubMed  CAS  Google Scholar 

  120. Santolini, E., et al. (2000) Numb is an endocytic protein. J. Cell. Biol. 151, 1345–1352.

    PubMed  CAS  Google Scholar 

  121. Frise, E., et al. (1996) The Drosophila NuMb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proc. Natl. Acad. Sci. U. S. A. 93,21): p. 11925–32.

    PubMed  CAS  Google Scholar 

  122. Guo, M., Jan, L. Y. and Jan, Y. N. (1996) Control of daughter cell fates during asymmetric division: interaction of Numb and Notch. Neuron 17, 27–41.

    PubMed  Google Scholar 

  123. Berdnik, D., et al. (2002) The endocytic protein alpha-Adaptin is required for nuMb-mediated asymmetric cell division in Drosophila. Dev. Cell 3, 221–231.

    PubMed  CAS  Google Scholar 

  124. McPherson, P. S., et al. (1996) A presynaptic inositol-5-phosphatase. Nature 379, 353–357.

    PubMed  CAS  Google Scholar 

  125. Haffner, C., et al. (1997) Synaptojanin 1: localization on coated endocytic intermediates in nerve terminals and interaction of its 170 kDa isoform with Eps15. FEBS Lett. 419, 175–180.

    PubMed  CAS  Google Scholar 

  126. Cremona, O., et al. (1999) Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 99, 179–188.

    PubMed  CAS  Google Scholar 

  127. Cleves, A. E., Novick, P. J., and Bankaitis, V. A. (1989) Mutations in the SAC1 gene suppress defects in yeast Golgi and yeast actin function. J. Cell. Biol. 109, 2939–2950.

    PubMed  CAS  Google Scholar 

  128. de Heuvel, E., et al. (1997) Identification of the major synaptojanin-binding proteins in brain. J. Biol. Chem. 272, 8710–8716.

    PubMed  Google Scholar 

  129. Reutens, A. T. and Begley, C. G. (2002) Endophilin-1: a multifunctional protein. Int. J. Biochem. Cell. Biol. 34, 1173–1177.

    PubMed  CAS  Google Scholar 

  130. Srinivasan, S., et al. (1997) Disruption of three phosphatidylinositol-polyphosphate 5-phosphatase genes from Saccharomyces cerevisiae results in pleiotropic abnormalities of vacuole morphology, cell shape, and osmohomeostasis. Eur J. Cell. Biol. 74, 350–360.

    PubMed  CAS  Google Scholar 

  131. Singer-Kruger, B., et al. (1998) Synaptojanin family members are implicated in endocytic membrane traffic in yeast. J. Cell Sci. 111, 3347–3356.

    PubMed  CAS  Google Scholar 

  132. De Camilli, P., et al. (2002) The ENTH domain. FEBS Lett. 513, 11–18.

    PubMed  Google Scholar 

  133. Chen, H., et al. (1998) Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature 394, 793–797.

    PubMed  CAS  Google Scholar 

  134. Itoh, T., et al. (2001) Role of the ENTH domain in phosphatidylinositol-4,5-bisphosphate binding and endocytosis. Science 291, 1047–1051.

    PubMed  CAS  Google Scholar 

  135. Wendland, B., (2002) Epsins: adaptors in endocytosis? Nat. Rev. Mol. Cell. Biol. 3, 971–977.

    PubMed  CAS  Google Scholar 

  136. Lohi, O., et al. (2002) VHS domain—a long-shoreman of vesicle lines. FEBS Lett. 513, 19–23.

    PubMed  CAS  Google Scholar 

  137. Lohi, O. and Lehto, V. P. (1998) VHS domain marks a group of proteins involved in endocytosis and vesicular trafficking. FEBS Lett. 440, 255–257.

    PubMed  CAS  Google Scholar 

  138. Steen, H., et al. (2002) Tyrosine phosphorylation mapping of the epidermal growth factor receptor signaling pathway. J. Biol. Chem. 277, 1031–1039.

    PubMed  CAS  Google Scholar 

  139. Bean, A. J., et al. (2000) Hrs-2 regulates receptor-mediated endocytosis via interactions with Eps15. J. Biol. Chem. 275, 15271–15278.

    PubMed  CAS  Google Scholar 

  140. Ahle, S. and Ungewickell, E. (1986) Purification and properties of a new clathrin assembly protein. EMBO J. 5, 3143–3149.

    PubMed  CAS  Google Scholar 

  141. Morris, S. A., et al. (1993) Clathrin assembly protein AP180: primary structure, domain organization and identification of a clathrin binding site. EMBO J. 12, 667–675.

    PubMed  CAS  Google Scholar 

  142. Tebar, F., Bohlander, S. K., and Sorkin, A. (1999) Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic. Mol. Biol. Cell. 10, 2687–2702.

    PubMed  CAS  Google Scholar 

  143. Ford, M. G., et al. (2001) Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science 291, 1051–1055.

    PubMed  CAS  Google Scholar 

  144. Ford, M. G., et al. (2002) Curvature of clathrin-coated pits driven by epsin. Nature 419, 361–366.

    PubMed  CAS  Google Scholar 

  145. Stahelin, R. V., et al. (2003) Contrasting membrane interaction mechanisms of AP180 N-terminal homology (ANTH) and epsin N-terminal homology (ENTH) domains. J. Biol. Chem. 278, 28993–28999.

    PubMed  CAS  Google Scholar 

  146. Baggett, J. J., DiAquino, K. E., and Wendland, B. (2003) The Sla2p Talin Homology Domain plays a role in Endocytosis in Saccharomyces cerevisiae. Genetics. 165, 1661–1674.

    PubMed  CAS  Google Scholar 

  147. Zhang, B., et al. (1998) Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis. Neuron 21, 1465–1475.

    PubMed  CAS  Google Scholar 

  148. Engqvist-Goldstein, A. E., et al. (1999) An actin-binding protein of the Sla2/Huntingtin interacting protein 1 family is a novel component of clathrin-coated pits and vesicles. J. Cell. Biol. 147, 1503–1518.

    PubMed  CAS  Google Scholar 

  149. Engqvist-Goldstein, A. E., et al. (2001) The actin-binding protein Hip1R associates with clathrin during early stages of endocytosis and promotes clathrin assembly in vitro. J. Cell. Biol. 154, 1209–1223.

    PubMed  CAS  Google Scholar 

  150. Mishra, S. K., et al. (2001) Clathrin- and AP-2-binding sites in HIP1 uncover a general assembly role for endocytic accessory proteins. J. Biol. Chem. 276, 46230–46236.

    PubMed  CAS  Google Scholar 

  151. Waelter, S., et al. (2001) The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis. Human Mol. Genet. 10, 1807–1817.

    CAS  Google Scholar 

  152. Metzler, M., et al. (2001) HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2. J. Biol. Chem. 276, 39271–19276.

    PubMed  CAS  Google Scholar 

  153. Legendre-Guillemin, V., et al. (2002) HIP1 and HIP12 display differential binding to F-actin, AP2, and clathrin. Identification of a novel interaction with clathrin light chain. J. Biol. Chem. 277, 19897–19904.

    PubMed  CAS  Google Scholar 

  154. Henry, K. R., et al. (2002) Scd5p and clathrin function are important for cortical actin organization, endocytosis, and localization of sla2p in yeast. Mol. Biol. Cell. 13, 2607–2625.

    PubMed  CAS  Google Scholar 

  155. Tang, H. Y., Xu, J., and Cai, M. (2000) Pan1p, End3p, and Sla1p, three yeast proteins required for normal cortical actin cytoskeleton organization, associate with each other and play essential roles in cell wall morphogenesis. Mol. Cell. Biol. 20, 12–25.

    Article  PubMed  CAS  Google Scholar 

  156. Howard, J. P., et al. (2002) Sla1p serves as the targeting signal recognition factor for NPFX(1,2)D-mediated endocytosis. J. Cell. Biol. 157, 315–326.

    PubMed  CAS  Google Scholar 

  157. Tan, P. K., Howard, J. P., and Payne, G. S. (1996) The sequence NPFXD defines a new class of endocytosis signal in Saccharomyces cerevisiae. J. Cell. Biol. 135, 1789–1800.

    PubMed  CAS  Google Scholar 

  158. Goode, B. L., et al. (2001) Activation of the Arp2/3 complex by the actin filament binding protein Abp1p. J. Cell. Biol. 153, 627–634.

    PubMed  CAS  Google Scholar 

  159. Li, R. (1997) Bee1, a yeast protein with homology to Wiscott-Aldrich syndrome protein, is critical for the assembly of cortical actin cytoskeleton. J. Cell. Biol. 136, 649–658.

    PubMed  CAS  Google Scholar 

  160. Smythe, E. and Ayscough, K. R. (2003) The Ark1/Prk1 family of protein kinases. Regulators of endocytosis and the actin skeleton. EMBO Rep. 4, 246–251.

    PubMed  CAS  Google Scholar 

  161. Zeng, G. and Cai, M. (1999) Regulation of the actin cytoskeleton organization in yeast by a novel serine/threonine kinase Prk1p. J. Cell. Biol. 144, 71–82.

    PubMed  CAS  Google Scholar 

  162. Zeng, G., Yu, X., and Cai, M. (2001) Regulation of yeast actin cytoskeleton-regulatory complex Pan1p/Sla1p/End3p by serine/threonine kinase Prk1p. Mol. Biol. Cell. 12, 3759–3772.

    PubMed  CAS  Google Scholar 

  163. Cope, M. J., et al. (1999) Novel protein kinases Ark1p and Prk1p associate with and regulate the cortical actin cytoskeleton in budding yeast. J. Cell. Biol. 144, 1203–1218.

    PubMed  CAS  Google Scholar 

  164. Watson, H. A., et al. (2001) In vivo role for actin-regulating kinases in endocytosis and yeast epsin phosphorylation. Mol. Biol. Cell. 12, 3668–3679.

    PubMed  CAS  Google Scholar 

  165. Korolchuk, V. I. and Banting, G. (2002) CK2 and GAK/auxilin2 are major protein kinases in clathrin-coated vesicles. Traffic 3, 428–439.

    PubMed  CAS  Google Scholar 

  166. Conner, S. D. and Schmid, S. L. (2002) Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. J. Cell. Biol. 156, 921–929.

    PubMed  CAS  Google Scholar 

  167. Olusanya, O., et al. (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, 896–900.

    PubMed  CAS  Google Scholar 

  168. Cousin, M. A. and Robinson, P. J. (2001) The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis. Trends Neurosci. 24, 659–665.

    PubMed  CAS  Google Scholar 

  169. Chen, H., et al. (1999) The interaction of epsin and Eps15 with the clathrin adaptor AP-2 is inhibited by mitotic phosphorylation and enhanced by stimulation-dependent dephosphorylation in nerve terminals. J. Biol. Chem. 274, 3257–3260.

    PubMed  CAS  Google Scholar 

  170. Rohatgi, R., Ho, H. Y., and Kirschner, M. W. (2000) Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate. J. Cell. Biol. 150, 1299–1310.

    PubMed  CAS  Google Scholar 

  171. Pruitt, W. M., et al. (2003) Role of the pleckstrin homology domain in intersectin-L Dbl homology domain activation of Cdc42 and signaling. Biochim Biophys Acta, 1640,1): p. 61–8.

    PubMed  CAS  Google Scholar 

  172. Zamanian, J. L. and Kelly R.B. (2003) Intersectin 1L guanine nucleotide exchange activity is regulated by adjacent src homology 3 domains that are also involved in endocytosis. Mol. Biol. Cell. 14, 1624–1637.

    PubMed  CAS  Google Scholar 

  173. Miliaras, N. B., Park, H. S., McCaffery, J. M., Wendland, B. Submitted.

  174. Tebar, F., et al. (1997) Eps15 is constitutively oligomerized due to homophilic interaction of its coiled-coil region. J. Biol. Chem. 272, 15413–15418.

    PubMed  CAS  Google Scholar 

  175. Cupers, P., et al. (1997) Parallel dimers and anti-parallel tetramers formed by epidermal growth factor receptor pathway substrate clone 15. J. Biol. Chem. 272, 33430–33434.

    PubMed  CAS  Google Scholar 

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Miliaras, N.B., Wendland, B. EH proteins. Cell Biochem Biophys 41, 295–318 (2004). https://doi.org/10.1385/CBB:41:2:295

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