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Gene Review

SH3GL2  -  SH3-domain GRB2-like 2

Homo sapiens

Synonyms: CNSA2, EEN-B1, Endophilin-1, Endophilin-A1, SH3 domain protein 2A, ...
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Disease relevance of SH3GL2

  • Knock-down of endophilin with small interfering RNA (siRNA) had no effect on virion production, but overexpression of endophilin and, to a lesser extent, of several fragments of the protein, result in inhibition of Mo-MuLV virion production, but not of HIV virion production [1].
  • The findings imply that endophilin is another component of the large complex that is hijacked by retroviruses to promote virion production [1].
  • RESULTS: A search for novel partners interacting with the Gag protein of the Moloney murine leukemia virus (Mo-MuLV) via the yeast two-hybrid protein-protein interaction assay resulted in the identification of endophilin 2, a component of the machinery involved in clathrin-mediated endocytosis [1].
  • Endophilin I expression is increased in Alzheimer's disease patients [2]

High impact information on SH3GL2

  • We report here a direct interaction between voltage-gated Ca2+ channels and endophilin, a key regulator of clathrin-mediated synaptic vesicle endocytosis [3].
  • Introduction into hippocampal neurons of a dominant-negative endophilin construct, which constitutively binds to Ca2+ channels, significantly reduces endocytosis-mediated uptake of FM 4-64 dye without abolishing exocytosis [3].
  • Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors [4].
  • Here we show that endophilin I is essential for the formation of synaptic-like microvesicles (SLMVs) from the plasma membrane [5].
  • Here, we demonstrate that Arc/Arg3.1 protein interacts with dynamin and specific isoforms of endophilin to enhance receptor endocytosis [6].

Biological context of SH3GL2

  • Endophilin dimerises through its N-terminus, and participates at multiple stages in clathrin-coated endocytosis, from early membrane invagination to synaptic vesicle uncoating [7].
  • Therefore, endophilin-1 may serve to couple vesicle biogenesis with intracellular signalling cascades [7].
  • The dramatic effects of the SH3 domain of endophilin led us to propose a model for the temporal order of addition of endophilin and its binding partner synaptojanin in the coated vesicle cycle [8].
  • SH3GL2, which was one of the 15 special genes, was located at one of the special chromosome regions, 9p12-pter [9].
  • This interaction served as an autophosphorylation-dependent scaffold to allow Src phosphorylation of endophilin A2 at Tyr315 [10].

Anatomical context of SH3GL2

  • Generation of high curvature membranes mediated by direct endophilin bilayer interactions [11].
  • Endophilin B, a protein with homology to endophilin 1, partially localizes to the Golgi complex and also deforms lipid bilayers into tubules, underscoring a potential role of endophilin family members in diverse tubulovesicular membrane-trafficking events in the cell [11].
  • In the brain, EEN-B1 and EEN-B2 mRNA are preferentially expressed in the cerebellar Purkinje and granule cells, dentate gyrus cells, hippocampal pyramidal neurons and cerebral granule cells [12].
  • Endophilin regulates JNK activation through its interaction with the germinal center kinase-like kinase [13].
  • Fission and uncoating of synaptic clathrin-coated vesicles are perturbed by disruption of interactions with the SH3 domain of endophilin [14].

Associations of SH3GL2 with chemical compounds


Physical interactions of SH3GL2


Co-localisations of SH3GL2


Other interactions of SH3GL2

  • In addition to synaptic vesicle formation, endophilin-1 complexes with signalling molecules, including cell surface receptors, metalloprotease disintegrins and germinal centre kinase-like kinase (GLK) [7].
  • They also recruit CIN85-endophilin in the complex with activated receptors, thus controlling receptor endocytosis [21].
  • By using mAb 806, which recognizes an EGFR-activation state and preferentially immunoprecipitates DeltaEGFR, we show that DeltaEGFR did not interact with Cbls, SETA, or endophilin A1, providing a mechanistic explanation for its lack of internalization [22].
  • EEN is a member of the endocytic endophilin family but its function in regulating endocytosis remains unclear [23].
  • In this issue of Neuron, Schuske et al. and Verstreken et al. show that the lipid-modifying enzyme endophilin recruits and stabilizes the polyphosphoinositide phosphatase synaptojanin at nerve terminals [24].

Analytical, diagnostic and therapeutic context of SH3GL2


  1. Endophilins interact with Moloney murine leukemia virus Gag and modulate virion production. Wang, M.Q., Kim, W., Gao, G., Torrey, T.A., Morse, H.C., De Camilli, P., Goff, S.P. J. Biol. (2003) [Pubmed]
  2. Endophilin I expression is increased in the brains of Alzheimer disease patients. Ren, Y., Xu, H.W., Davey, F., Taylor, M., Aiton, J., Coote, P., Fang, F., Yao, J., Chen, D., Chen, J.X., Yan, S.D., Gunn-Moore, F.J. J. Biol. Chem. (2008) [Pubmed]
  3. Formation of an endophilin-Ca2+ channel complex is critical for clathrin-mediated synaptic vesicle endocytosis. Chen, Y., Deng, L., Maeno-Hikichi, Y., Lai, M., Chang, S., Chen, G., Zhang, J.F. Cell (2003) [Pubmed]
  4. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Soubeyran, P., Kowanetz, K., Szymkiewicz, I., Langdon, W.Y., Dikic, I. Nature (2002) [Pubmed]
  5. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Schmidt, A., Wolde, M., Thiele, C., Fest, W., Kratzin, H., Podtelejnikov, A.V., Witke, W., Huttner, W.B., Söling, H.D. Nature (1999) [Pubmed]
  6. Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Chowdhury, S., Shepherd, J.D., Okuno, H., Lyford, G., Petralia, R.S., Plath, N., Kuhl, D., Huganir, R.L., Worley, P.F. Neuron (2006) [Pubmed]
  7. Endophilin-1: a multifunctional protein. Reutens, A.T., Begley, C.G. Int. J. Biochem. Cell Biol. (2002) [Pubmed]
  8. The role of dynamin and its binding partners in coated pit invagination and scission. Hill, E., van Der Kaay, J., Downes, C.P., Smythe, E. J. Cell Biol. (2001) [Pubmed]
  9. Average-12.9 chromosome imbalances coupling with 15 differential expression genes possibly involved in the carcinogenesis, progression and metastasis of supraglottic laryngeal squamous cell cancer. Fu, W.N., Shang, C., Huang, D.F., Xu, Z.M., Sun, X.H., Sun, K.L. Zhonghua Yi Xue Yi Chuan Xue Za Zhi (2006) [Pubmed]
  10. FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation. Wu, X., Gan, B., Yoo, Y., Guan, J.L. Dev. Cell (2005) [Pubmed]
  11. Generation of high curvature membranes mediated by direct endophilin bilayer interactions. Farsad, K., Ringstad, N., Takei, K., Floyd, S.R., Rose, K., De Camilli, P. J. Cell Biol. (2001) [Pubmed]
  12. Expression and protein-binding studies of the EEN gene family, new interacting partners for dynamin, synaptojanin and huntingtin proteins. So, C.W., Sham, M.H., Chew, S.L., Cheung, N., So, C.K., Chung, S.K., Caldas, C., Wiedemann, L.M., Chan, L.C. Biochem. J. (2000) [Pubmed]
  13. Endophilin regulates JNK activation through its interaction with the germinal center kinase-like kinase. Ramjaun, A.R., Angers, A., Legendre-Guillemin, V., Tong, X.K., McPherson, P.S. J. Biol. Chem. (2001) [Pubmed]
  14. Fission and uncoating of synaptic clathrin-coated vesicles are perturbed by disruption of interactions with the SH3 domain of endophilin. Gad, H., Ringstad, N., Löw, P., Kjaerulff, O., Gustafsson, J., Wenk, M., Di Paolo, G., Nemoto, Y., Crun, J., Ellisman, M.H., De Camilli, P., Shupliakov, O., Brodin, L. Neuron (2000) [Pubmed]
  15. The SH3 domains of endophilin and amphiphysin bind to the proline-rich region of synaptojanin 1 at distinct sites that display an unconventional binding specificity. Cestra, G., Castagnoli, L., Dente, L., Minenkova, O., Petrelli, A., Migone, N., Hoffmüller, U., Schneider-Mergener, J., Cesareni, G. J. Biol. Chem. (1999) [Pubmed]
  16. Sequential steps in clathrin-mediated synaptic vesicle endocytosis. Brodin, L., Löw, P., Shupliakov, O. Curr. Opin. Neurobiol. (2000) [Pubmed]
  17. The HECT domain ligase itch ubiquitinates endophilin and localizes to the trans-Golgi network and endosomal system. Angers, A., Ramjaun, A.R., McPherson, P.S. J. Biol. Chem. (2004) [Pubmed]
  18. Modulation of membrane curvature by phosphatidic acid and lysophosphatidic acid. Kooijman, E.E., Chupin, V., de Kruijff, B., Burger, K.N. Traffic (2003) [Pubmed]
  19. Dynamin: characteristics, mechanism of action and function. Wiejak, J., Wyroba, E. Cell. Mol. Biol. Lett. (2002) [Pubmed]
  20. Identification of Endophilins 1 and 3 as Selective Binding Partners for VGLUT1 and Their Co-Localization in Neocortical Glutamatergic Synapses: Implications for Vesicular Glutamate Transporter Trafficking and Excitatory Vesicle Formation. De Gois, S., Jeanclos, E., Morris, M., Grewal, S., Varoqui, H., Erickson, J.D. Cell. Mol. Neurobiol. (2006) [Pubmed]
  21. Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors. Haglund, K., Shimokawa, N., Szymkiewicz, I., Dikic, I. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  22. Epidermal growth factor receptor signaling intensity determines intracellular protein interactions, ubiquitination, and internalization. Schmidt, M.H., Furnari, F.B., Cavenee, W.K., Bögler, O. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  23. Activation of EGF receptor endocytosis and ERK1/2 signaling by BPGAP1 requires direct interaction with EEN/endophilin II and a functional RhoGAP domain. Lua, B.L., Low, B.C. J. Cell. Sci. (2005) [Pubmed]
  24. Endophilin and synaptojanin hook up to promote synaptic vesicle endocytosis. Song, W., Zinsmaier, K.E. Neuron (2003) [Pubmed]
  25. Study of the SH3-domain GRB2-like 2 gene expression in laryngeal carcinoma. Shang, C., Fu, W.N., Guo, Y., Huang, D.F., Sun, K.L. Chin. Med. J. (2007) [Pubmed]
  26. Synaptojanin forms two separate complexes in the nerve terminal. Interactions with endophilin and amphiphysin. Micheva, K.D., Kay, B.K., McPherson, P.S. J. Biol. Chem. (1997) [Pubmed]
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