adaptor protein complex 2


Summary: An adaptor protein complex primarily involved in the formation of clathrin-related endocytotic vesicles (ENDOSOMES) at the CELL MEMBRANE.

Top Publications

  1. Pan C, Baum P, Gu M, Jorgensen E, Clark S, Garriga G. C. elegans AP-2 and retromer control Wnt signaling by regulating mig-14/Wntless. Dev Cell. 2008;14:132-9 pubmed
    ..By contrast, MIG-14 accumulates in intracellular compartments in retromer mutants. Based on our observations, we propose that intracellular trafficking of MIG-14 by AP-2 and retromer plays an important role in Wnt secretion. ..
  2. Lindwasser O, Smith W, Chaudhuri R, Yang P, Hurley J, Bonifacino J. A diacidic motif in human immunodeficiency virus type 1 Nef is a novel determinant of binding to AP-2. J Virol. 2008;82:1166-74 pubmed
  3. Kim S, Ryan T. A distributed set of interactions controls mu2 functionality in the role of AP-2 as a sorting adaptor in synaptic vesicle endocytosis. J Biol Chem. 2009;284:32803-12 pubmed publisher
    ..These data thus indicate that AP-2 plays a role in cargo selection but that no single aspect of mu2 function is critical, implying that a more distributed network of interactions supports AP-2 function in SV endocytosis. ..
  4. Yu A, Rual J, Tamai K, Harada Y, Vidal M, He X, et al. Association of Dishevelled with the clathrin AP-2 adaptor is required for Frizzled endocytosis and planar cell polarity signaling. Dev Cell. 2007;12:129-41 pubmed
    ..We suggest that the direct interaction of Dvl2 with AP-2 is important for Frizzled internalization and Frizzled/PCP signaling. ..
  5. Motley A, Bright N, Seaman M, Robinson M. Clathrin-mediated endocytosis in AP-2-depleted cells. J Cell Biol. 2003;162:909-18 pubmed
    ..Uptake of the EGF and LDL receptors may be facilitated by alternative adaptors...
  6. Boll W, Rapoport I, Brunner C, Modis Y, Prehn S, Kirchhausen T. The mu2 subunit of the clathrin adaptor AP-2 binds to FDNPVY and YppØ sorting signals at distinct sites. Traffic. 2002;3:590-600 pubmed
    ..These results suggest the possibility that low-density lipoprotein receptor uptake may be modulated specifically and independently of other proteins in the clathrin pathway. ..
  7. Brett T, Traub L, Fremont D. Accessory protein recruitment motifs in clathrin-mediated endocytosis. Structure. 2002;10:797-809 pubmed
    ..A mechanism of clathrin assembly regulation is suggested by three different AP-2 engagement modes. ..
  8. Jha A, Agostinelli N, Mishra S, Keyel P, Hawryluk M, Traub L. A novel AP-2 adaptor interaction motif initially identified in the long-splice isoform of synaptojanin 1, SJ170. J Biol Chem. 2004;279:2281-90 pubmed
    ..These interactions likely contribute to the appropriate targeting of certain endocytic components to clathrin bud sites assembling at the cell surface. ..
  9. Traub L. Sorting it out: AP-2 and alternate clathrin adaptors in endocytic cargo selection. J Cell Biol. 2003;163:203-8 pubmed
    ..Remarkably, AP-2 is not obligatory for all clathrin-mediated uptake, and several alternate adaptors appear to perform similar sorting and assembly functions at the clathrin bud site...

More Information


  1. Wagener B, Marjon N, Revankar C, Prossnitz E. Adaptor protein-2 interaction with arrestin regulates GPCR recycling and apoptosis. Traffic. 2009;10:1286-300 pubmed publisher
  2. Mitsunari T, Nakatsu F, Shioda N, Love P, Grinberg A, Bonifacino J, et al. Clathrin adaptor AP-2 is essential for early embryonal development. Mol Cell Biol. 2005;25:9318-23 pubmed
    ..5 postcoitus (E3.5). These results indicate that AP-2 is indispensable for early embryonic development, which might be due to its requirement for cell viability. ..
  3. Aguilar R, Ohno H, Roche K, Bonifacino J. Functional domain mapping of the clathrin-associated adaptor medium chains mu1 and mu2. J Biol Chem. 1997;272:27160-6 pubmed
  4. Sorkin A. Cargo recognition during clathrin-mediated endocytosis: a team effort. Curr Opin Cell Biol. 2004;16:392-9 pubmed
    ..These alternative mechanisms appear to be particularly important during clathrin-mediated endocytosis of signaling receptors...
  5. Boucrot E, Saffarian S, Zhang R, Kirchhausen T. Roles of AP-2 in clathrin-mediated endocytosis. PLoS ONE. 2010;5:e10597 pubmed publisher
    ..We also show that under certain conditions of stress, cells can upregulate alternative endocytic structures with the potential to provide compensatory trafficking pathways. ..
  6. Jackson L, Kelly B, McCoy A, Gaffry T, James L, Collins B, et al. A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex. Cell. 2010;141:1220-9 pubmed publisher
    ..Using a range of biophysical techniques, we show that the endocytic cargo binding of AP2 is driven by its interaction with PtdIns4,5P(2)-containing membranes. ..
  7. Semerdjieva S, Shortt B, Maxwell E, Singh S, Fonarev P, Hansen J, et al. Coordinated regulation of AP2 uncoating from clathrin-coated vesicles by rab5 and hRME-6. J Cell Biol. 2008;183:499-511 pubmed publisher
    ..These data are consistent with a model in which hRME-6 and rab5 regulate AP2 uncoating in vivo by coordinately regulating mu2 dephosphorylation and PtdIns(4,5)P(2) levels in CCVs. ..
  8. Chaudhuri R, Lindwasser O, Smith W, Hurley J, Bonifacino J. Downregulation of CD4 by human immunodeficiency virus type 1 Nef is dependent on clathrin and involves direct interaction of Nef with the AP2 clathrin adaptor. J Virol. 2007;81:3877-90 pubmed
    ..Together, these results support a model in which HIV-1 Nef downregulates CD4 by promoting its accelerated endocytosis by a clathrin/AP2 pathway. ..
  9. Ball C, Hunt S, Robinson M. Expression and localization of alpha-adaptin isoforms. J Cell Sci. 1995;108 ( Pt 8):2865-75 pubmed
    ..This suggests that alpha C may play more of a role in the recycling of membrane components throughout the cell. ..
  10. Conner S, Schmid S. Differential requirements for AP-2 in clathrin-mediated endocytosis. J Cell Biol. 2003;162:773-9 pubmed
    ..Surprisingly, clathrin distribution and EGF uptake were unaffected by AAK1 overexpression. Thus, AP-2 may not be stoichiometrically required for coat assembly, and may have a more cargo-selective function in CME than previously thought...
  11. Mishra S, Hawryluk M, Brett T, Keyel P, Dupin A, Jha A, et al. Dual engagement regulation of protein interactions with the AP-2 adaptor alpha appendage. J Biol Chem. 2004;279:46191-203 pubmed
  12. Noble B, Abada P, Nunez Iglesias J, Cannon P. Recruitment of the adaptor protein 2 complex by the human immunodeficiency virus type 2 envelope protein is necessary for high levels of virus release. J Virol. 2006;80:2924-32 pubmed
  13. Byland R, Vance P, Hoxie J, Marsh M. A conserved dileucine motif mediates clathrin and AP-2-dependent endocytosis of the HIV-1 envelope protein. Mol Biol Cell. 2007;18:414-25 pubmed
  14. Eto D, Gordon H, Dhakal B, Jones T, Mulvey M. Clathrin, AP-2, and the NPXY-binding subset of alternate endocytic adaptors facilitate FimH-mediated bacterial invasion of host cells. Cell Microbiol. 2008;10:2553-67 pubmed publisher
  15. Collins B, McCoy A, Kent H, Evans P, Owen D. Molecular architecture and functional model of the endocytic AP2 complex. Cell. 2002;109:523-35 pubmed
    ..A model for AP2 recruitment and activation is proposed. ..
  16. Gu M, Schuske K, Watanabe S, Liu Q, Baum P, Garriga G, et al. Mu2 adaptin facilitates but is not essential for synaptic vesicle recycling in Caenorhabditis elegans. J Cell Biol. 2008;183:881-92 pubmed publisher
    ..Collectively, these data suggest AP2 micro2 facilitates but is not essential for synaptic vesicle recycling. ..
  17. Cihil K, Ellinger P, Fellows A, Stolz D, Madden D, Swiatecka Urban A. Disabled-2 protein facilitates assembly polypeptide-2-independent recruitment of cystic fibrosis transmembrane conductance regulator to endocytic vesicles in polarized human airway epithelial cells. J Biol Chem. 2012;287:15087-99 pubmed publisher
    ..These effects are mediated by the DAB homology domain. Moreover, we show that in human airway epithelial cells AP-2 is not essential for CFTR recruitment to CCVs. ..
  18. Lee J, Jongeward G, Sternberg P. unc-101, a gene required for many aspects of Caenorhabditis elegans development and behavior, encodes a clathrin-associated protein. Genes Dev. 1994;8:60-73 pubmed
    ..We have sequenced the mutant alleles of unc-101 identified in various genetic screens and shown that all but one are deletions or nonsense mutations, suggesting that these alleles severely reduce unc-101 function...
  19. Mishra S, Keyel P, Hawryluk M, Agostinelli N, Watkins S, Traub L. Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor. EMBO J. 2002;21:4915-26 pubmed
  20. Conner S, Schmid S. Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. J Cell Biol. 2002;156:921-9 pubmed
    ..These results also lend support to the idea that clathrin-mediated endocytosis is controlled by cycles of phosphorylation/desphosphorylation. ..
  21. Nakano Kobayashi A, Yamazaki M, Unoki T, Hongu T, Murata C, Taguchi R, et al. Role of activation of PIP5Kgamma661 by AP-2 complex in synaptic vesicle endocytosis. EMBO J. 2007;26:1105-16 pubmed
    ..These findings provide evidence for the molecular mechanism through which PIP5Kgamma661 locally generates PI(4,5)P2 in hippocampal neurons and suggest a model in which the interaction trigger SV endocytosis. ..
  22. Olusanya O, Andrews P, Swedlow J, Smythe E. Phosphorylation of threonine 156 of the mu2 subunit of the AP2 complex is essential for endocytosis in vitro and in vivo. Curr Biol. 2001;11:896-900 pubmed
    ..Here, we show that phosphorylation of a single threonine residue (Thr156) of the mu2 subunit of the AP2 complex is essential for efficient endocytosis of transferrin both in an in vitro coated-pit budding assay and in living cells...
  23. Owen D, Vallis Y, Noble M, Hunter J, Dafforn T, Evans P, et al. A structural explanation for the binding of multiple ligands by the alpha-adaptin appendage domain. Cell. 1999;97:805-15 pubmed
    ..A single site for binding multiple ligands would allow for temporal and spatial regulation in the recruitment of components of the endocytic machinery. ..
  24. Praefcke G, Ford M, Schmid E, Olesen L, Gallop J, Peak Chew S, et al. Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis. EMBO J. 2004;23:4371-83 pubmed
    ..In the final coated vesicle, most appendage binding partners are absent and thus the functional status of the appendage domain as an interaction hub is temporal and transitory giving directionality to vesicle assembly. ..
  25. Kirchhausen T, Davis A, Frucht S, Greco B, Payne G, Tubb B. AP17 and AP19, the mammalian small chains of the clathrin-associated protein complexes show homology to Yap17p, their putative homolog in yeast. J Biol Chem. 1991;266:11153-7 pubmed
    ..The yeast sequence predicts Yap17p, a protein with 147 amino acids and a Mr of 17,373 that is slightly more related to the mammalian AP17 chain than to its AP19 counterpart. ..
  26. Owen D, Evans P. A structural explanation for the recognition of tyrosine-based endocytotic signals. Science. 1998;282:1327-32 pubmed
    ..Specificity was conferred by hydrophobic pockets that bind the tyrosine and leucine in the peptide. In the crystal, the protein forms dimers that could increase the strength and specificity of binding to dimeric receptors. ..
  27. Chen B, Siderovski D, Neubig R, Lawson M, Trejo J. Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins. J Biol Chem. 2014;289:1580-91 pubmed publisher
    ..Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than ?-arrestins...
  28. Honing S, Ricotta D, Krauss M, Späte K, Spolaore B, Motley A, et al. Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2. Mol Cell. 2005;18:519-31 pubmed
    ..The binding of AP2 to acidic-dileucine motifs occurs at a different site from Yxxvarphi binding and is not enhanced by mu2Thr156 phosphorylation. ..
  29. Keyel P, Mishra S, Roth R, Heuser J, Watkins S, Traub L. A single common portal for clathrin-mediated endocytosis of distinct cargo governed by cargo-selective adaptors. Mol Biol Cell. 2006;17:4300-17 pubmed
    ..However, Dab2 expression is exceptionally low in hepatocytes, likely accounting for the pathological hypercholesterolemia that accompanies ARH loss. ..
  30. Murshid A, Srivastava A, Kumar R, Presley J. Characterization of the localization and function of NECAP 1 in neurons. J Neurochem. 2006;98:1746-62 pubmed
    ..This inhibition was abrogated by truncation of the WVQF domain. We conclude from these observations that NECAP 1 plays a role in clathrin-mediated neuronal endocytosis, including a role in presynaptic endocytosis. ..
  31. Paing M, Johnston C, Siderovski D, Trejo J. Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol Cell Biol. 2006;26:3231-42 pubmed
    ..Our findings establish a novel role for AP2 in direct regulation of PAR1 trafficking, a process critically important to the temporal and spatial aspects of thrombin signaling. ..
  32. David C, McPherson P, Mundigl O, De Camilli P. A role of amphiphysin in synaptic vesicle endocytosis suggested by its binding to dynamin in nerve terminals. Proc Natl Acad Sci U S A. 1996;93:331-5 pubmed
    ..These findings support a role of amphiphysin in synaptic vesicle endocytosis. ..
  33. Gonzalez Gaitan M, Jackle H. Role of Drosophila alpha-adaptin in presynaptic vesicle recycling. Cell. 1997;88:767-76 pubmed
    ..Our results suggest an alpha-adaptin-dependent control of the vesicle cycle that maintains the balance between the amount of vesicle- and surface-associated membranes. ..
  34. Nesterov A, Carter R, Sorkina T, Gill G, Sorkin A. 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. 1999;18:2489-99 pubmed
  35. Rohde G, Wenzel D, Haucke V. A phosphatidylinositol (4,5)-bisphosphate binding site within mu2-adaptin regulates clathrin-mediated endocytosis. J Cell Biol. 2002;158:209-14 pubmed
    ..We suggest that PI(4,5)P2 binding to mu2-adaptin regulates clathrin-mediated endocytosis and thereby may contribute to structurally linking cargo recognition to coat formation. ..
  36. Geyer M, Yu H, Mandic R, Linnemann T, Zheng Y, Fackler O, et al. Subunit H of the V-ATPase binds to the medium chain of adaptor protein complex 2 and connects Nef to the endocytic machinery. J Biol Chem. 2002;277:28521-9 pubmed
    ..that V1H binds to the C-terminal flexible loop in Nef from HIV-1 and to the medium chain (mu2) of the adaptor protein complex 2 (AP-2) in vitro and in vivo...
  37. Page L, Robinson M. Targeting signals and subunit interactions in coated vesicle adaptor complexes. J Cell Biol. 1995;131:619-30 pubmed
    ..These results indicate that the adaptor subunits act in concert to target the complex to the appropriate membrane. ..
  38. Cocucci E, Aguet F, Boulant S, Kirchhausen T. The first five seconds in the life of a clathrin-coated pit. Cell. 2012;150:495-507 pubmed publisher
    ..This objective picture of coated pit initiation also shows that methods outlined here will be broadly useful for studies of dynamic assemblies in living cells. ..
  39. Mulkearns E, Cooper J. FCH domain only-2 organizes clathrin-coated structures and interacts with Disabled-2 for low-density lipoprotein receptor endocytosis. Mol Biol Cell. 2012;23:1330-42 pubmed publisher
    ..These results indicate FCHO2 regulates the size of clathrin structures, and its interaction with Dab2 is needed for LDLR endocytosis under conditions of low AP2. ..
  40. Núñez D, Antonescu C, Mettlen M, Liu A, Schmid S, Loerke D, et al. Hotspots organize clathrin-mediated endocytosis by efficient recruitment and retention of nucleating resources. Traffic. 2011;12:1868-78 pubmed publisher
  41. Ricotta D, Conner S, Schmid S, von Figura K, Honing S. Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals. J Cell Biol. 2002;156:791-5 pubmed
    ..We propose that phosphorylation of the AP2 mu 2 subunit by AAK1 ensures high affinity binding of AP2 to sorting signals of cargo membrane proteins during the initial steps of receptor-mediated endocytosis. ..
  42. Teckchandani A, Toida N, Goodchild J, Henderson C, Watts J, Wollscheid B, et al. Quantitative proteomics identifies a Dab2/integrin module regulating cell migration. J Cell Biol. 2009;186:99-111 pubmed publisher
  43. Lee S, Liu L, Wang Y, Sheng M. Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron. 2002;36:661-74 pubmed
    ..NSF function, on the other hand, is needed to maintain synaptic AMPA receptor responses, but is not directly required for NMDA receptor-mediated internalization and LTD. ..
  44. Rollason R, Korolchuk V, Hamilton C, Schu P, Banting G. Clathrin-mediated endocytosis of a lipid-raft-associated protein is mediated through a dual tyrosine motif. J Cell Sci. 2007;120:3850-8 pubmed
  45. Schmidt U, Briese S, Leicht K, Schurmann A, Joost H, Al Hasani H. Endocytosis of the glucose transporter GLUT8 is mediated by interaction of a dileucine motif with the beta2-adaptin subunit of the AP-2 adaptor complex. J Cell Sci. 2006;119:2321-31 pubmed
  46. Ford M, Pearse B, Higgins M, Vallis Y, Owen D, Gibson A, et al. Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science. 2001;291:1051-5 pubmed
    ..This was shown by using purified components and a budding assay on preformed lipid monolayers. In the presence of AP180, clathrin lattices formed on the monolayer. When AP2 was also present, coated pits were formed...
  47. Doray B, Knisely J, Wartman L, Bu G, Kornfeld S. Identification of acidic dileucine signals in LRP9 that interact with both GGAs and AP-1/AP-2. Traffic. 2008;9:1551-62 pubmed publisher
    ..Either AC-LL motif of LRP9 is functional in endocytosis. These findings represent the first study characterizing the trafficking of LRP9 and also have implications for the identification of additional GGA cargo molecules. ..
  48. Yu A, Xing Y, Harrison S, Kirchhausen T. Structural analysis of the interaction between Dishevelled2 and clathrin AP-2 adaptor, a critical step in noncanonical Wnt signaling. Structure. 2010;18:1311-20 pubmed publisher
    ..The crystal structure has thus allowed us to identify the specific interaction that leads to Frizzled uptake and to downstream, noncanonical signaling events. ..
  49. Huang F, Jiang X, Sorkin A. 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. 2003;278:43411-7 pubmed
    ..Surprisingly, mutation of the Leu-1010/Leu-1011 motif resulted in impaired degradation of EGF receptors, suggesting the role of this motif in lysosomal targeting of the receptor. ..
  50. Lundmark R, Carlsson S. Sorting nexin 9 participates in clathrin-mediated endocytosis through interactions with the core components. J Biol Chem. 2003;278:46772-81 pubmed
    ..SNX9 is one of the major proteins in hematopoietic cells that binds to the alpha and beta2-appendages of adaptor protein complex 2 (AP-2), a protein with a critical role in the formation of clathrin-coated vesicles at the plasma ..
  51. Geminard C, de Gassart A, Blanc L, Vidal M. Degradation of AP2 during reticulocyte maturation enhances binding of hsc70 and Alix to a common site on TFR for sorting into exosomes. Traffic. 2004;5:181-93 pubmed
    ..Finally, coimmunoprecipitation of Alix with the exosomal TfR, and binding of P1 peptide to the Alix homolog PalA suggest that Alix also interacts with the YTRF motif and contributes to exosomal TfR sorting. ..
  52. Kim S, Xu Z, Song K, Kim D, Kang H, Reichardt I, et al. Adaptor protein complex 2-mediated endocytosis is crucial for male reproductive organ development in Arabidopsis. Plant Cell. 2013;25:2970-85 pubmed publisher
    ..Here, we present evidence that endocytosis, involving heterotetrameric adaptor protein complex 2 (AP-2), plays a crucial role in fertilization...
  53. Chaudhuri R, Mattera R, Lindwasser O, Robinson M, Bonifacino J. A basic patch on alpha-adaptin is required for binding of human immunodeficiency virus type 1 Nef and cooperative assembly of a CD4-Nef-AP-2 complex. J Virol. 2009;83:2518-30 pubmed publisher
    ..This cooperativity explains how Nef is able to efficiently downregulate CD4 despite weak binary interactions between components of the tripartite complex. ..