Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Ameet S. Sengar
  • Michael W. Salter
  • Sean E. EganEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_440


The Intersectin Family

The Intersectin family refers to a group of proteins that share N-terminal EH domains, a central coiled-coil domain, and multiple SH3 domains. In mammals, there are Intersectin1 and 2 genes (Itsn1 and Itsn2, respectively), whereas in invertebrates, only one gene appears to be present.

Historical Background

Intersectins are conserved modular scaffold proteins with two Eps15-homology (EH) domains, an extended KLERQ coiled-coil domain, four or five Src-homology 3 (SH3) domains, and, in some vertebrate splice variants, DBL/PH and C2 domains (Fig. 1). The Itsn proteins were discovered independently in a number of organisms and in a number of labs. For example, the single Itsn in Drosophila melanogaster, Dap160, or Dynamin-associated protein 160 kDa, copurified with the proline-rich C-terminus of Dynamin (Roos and Kelly 1998). Human ITSN1 was cloned following identification of a trapped exon that coded for a novel EH domain (Guipponi et al. 1998...
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  1. Chabu C, Doe CQ. Dap160/intersectin binds and activates aPKC to regulate cell polarity and cell cycle progression. Development. 2008;135(16):2739–46.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Das M, Scappini E, Martin NP, Wong KA, Dunn S, Chen YJ, et al. Regulation of neuron survival through an intersectin-phosphoinositide 3′-kinase C2beta-AKT pathway. Mol Cell Biol. 2007;27(22):7906–17.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Evergren E, Gad H, Walther K, Sundborger A, Tomilin N, Shupliakov O. Intersectin is a negative regulator of dynamin recruitment to the synaptic endocytic zone in the central synapse. J Neurosci. 2007;27(2):379–90.CrossRefPubMedGoogle Scholar
  4. Ferguson SM, Raimondi A, Paradise S, Shen H, Mesaki K, Ferguson A, et al. Coordinated actions of actin and BAR proteins upstream of dynamin at endocytic clathrin-coated pits. Dev Cell. 2009;17(6):811–22.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Guipponi M, Scott HS, Hattori M, Ishii K, Sakaki Y, Antonarakis SE. Genomic structure, sequence, and refined mapping of the human intersectin gene (ITSN), which encompasses 250 kb on chromosome 21q22.1→q22.2. Cytogenet Cell Genet. 1998;83(3–4):218–20.CrossRefPubMedGoogle Scholar
  6. He G, Wang HR, Huang SK, Huang CL. Intersectin links WNK kinases to endocytosis of ROMK1. J Clin Invest. 2007;117(4):1078–87.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Henne WM, Boucrot E, Meinecke M, Evergren E, Vallis Y, Mittal R, et al. FCHo proteins are nucleators of clathrin-mediated endocytosis. Science. 2010;328:1281–4.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Hussain NK, Yamabhai M, Ramjaun AR, Guy AM, Baranes D, O’Bryan JP, et al. Splice variants of intersectin are components of the endocytic machinery in neurons and nonneuronal cells. J Biol Chem. 1999;274(22):15671–7.CrossRefPubMedGoogle Scholar
  9. Hussain NK, Jenna S, Glogauer M, Quinn CC, Wasiak S, Guipponi M, et al. Endocytic protein intersectin-l regulates actin assembly via Cdc42 and N-WASP. Nat Cell Biol. 2001;3(10):927–32.CrossRefPubMedGoogle Scholar
  10. Irie F, Yamaguchi Y. EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. Nat Neurosci. 2002;5(11):1117–8.CrossRefPubMedGoogle Scholar
  11. Khanna R, Li Q, Stanley EF. ‘Fractional recovery’ analysis of a presynaptic synaptotagmin 1-anchored endocytic protein complex. PLoS One. 2006;1:e67.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Khanna R, Li Q, Schlichter LC, Stanley EF. The transmitter release-site CaV2.2 channel cluster is linked to an endocytosis coat protein complex. Eur J Neurosci. 2007;26(3):560–74.CrossRefPubMedGoogle Scholar
  13. Khodosh R, Augsburger A, Schwarz TL, Garrity PA. Bchs, a BEACH domain protein, antagonizes Rab11 in synapse morphogenesis and other developmental events. Development. 2006;133(23):4655–65.CrossRefPubMedGoogle Scholar
  14. Klein I, Predescu D, Sharma T, Knezevic I, Malik A, Predescu S. Intersectin-2L regulates caveolae endocytosis secondary to Cdc42-mediated actin polymerization. J Biol Chem. 2009;284:25953.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Koh TW, Verstreken P, Bellen HJ. Dap160/intersectin acts as a stabilizing scaffold required for synaptic development and vesicle endocytosis. Neuron. 2004;43(2):193–205.CrossRefPubMedGoogle Scholar
  16. Koh TW, Korolchuk VI, Wairkar YP, Jiao W, Evergren E, Pan H, et al. Eps15 and Dap160 control synaptic vesicle membrane retrieval and synapse development. J Cell Biol. 2007;178(2):309–22.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Loeb CR, Harris JL, Craik CS. Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance toward apoptosis. J Biol Chem. 2006;281(38):28326–35.CrossRefPubMedGoogle Scholar
  18. Majumdar A, Ramagiri S, Rikhy R. Drosophila homologue of Eps15 is essential for synaptic vesicle recycling. Exp Cell Res. 2006;312(12):2288–98.CrossRefPubMedGoogle Scholar
  19. Malacombe M, Ceridono M, Calco V, Chasserot-Golaz S, McPherson PS, Bader MF, et al. Intersectin-1 L nucleotide exchange factor regulates secretory granule exocytosis by activating Cdc42. EMBO J. 2006;25(15):3494–503.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Marie B, Sweeney ST, Poskanzer KE, Roos J, Kelly RB, Davis GW. Dap160/intersectin scaffolds the periactive zone to achieve high-fidelity endocytosis and normal synaptic growth. Neuron. 2004;43(2):207–19.CrossRefPubMedGoogle Scholar
  21. Maritzen T, Podufall J, Haucke V. Stonins–specialized adaptors for synaptic vesicle recycling and beyond? Traffic. 2010;11(1):8–15.CrossRefPubMedGoogle Scholar
  22. McCabe BD, Marques G, Haghighi AP, Fetter RD, Crotty ML, Haerry TE, et al. The BMP homolog Gbb provides a retrograde signal that regulates synaptic growth at the Drosophila neuromuscular junction. Neuron. 2003;39(2):241–54.CrossRefPubMedGoogle Scholar
  23. McGavin MK, Badour K, Hardy LA, Kubiseski TJ, Zhang J, Siminovitch KA. The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis. J Exp Med. 2001;194(12):1777–87.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Mohney RP, Das M, Bivona TG, Hanes R, Adams AG, Philips MR, et al. Intersectin activates Ras but stimulates transcription through an independent pathway involving JNK. J Biol Chem. 2003;278(47):47038–45.CrossRefPubMedGoogle Scholar
  25. Nahm M, Kim S, Paik SK, Lee M, Lee S, Lee ZH, et al. dCIP4 (Drosophila Cdc42-interacting protein 4) restrains synaptic growth by inhibiting the secretion of the retrograde glass bottom boat signal. J Neurosci. 2010;30(24):8138–50.CrossRefPubMedGoogle Scholar
  26. Nakatsu F, Perera RM, Lucast L, Zoncu R, Domin J, Gertler FB, et al. The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics. J Cell Biol. 2010;190(3):307–15.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Nishimura T, Yamaguchi T, Tokunaga A, Hara A, Hamaguchi T, Kato K, et al. Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2. Mol Biol Cell. 2006;17(3):1273–85.PubMedPubMedCentralCrossRefGoogle Scholar
  28. O’Connor-Giles KM, Ho LL, Ganetzky B. Nervous wreck interacts with thickveins and the endocytic machinery to attenuate retrograde BMP signaling during synaptic growth. Neuron. 2008;58(4):507–18.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Okamoto M, Schoch S, Sudhof TC. EHSH1/intersectin, a protein that contains EH and SH3 domains and binds to dynamin and SNAP-25. A protein connection between exocytosis and endocytosis? J Biol Chem. 1999;274(26):18446–54.CrossRefPubMedGoogle Scholar
  30. Pechstein A, Bacetic J, Vahedi-Faridi A, Gromova K, Sundborger A, Tomlin N, et al. Regulation of synaptic vesicle recycling by complex formation between intersectin 1 and the clathrin adaptor complex AP2. Proc Natl Acad Sci U S A. 2010a;107:4206.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Pechstein A, Shupliakov O, Haucke V. Intersectin 1: a versatile actor in the synaptic vesicle cycle. Biochem Soc Trans. 2010b;038(1):181–6.CrossRefGoogle Scholar
  32. Predescu SA, Predescu DN, Timblin BK, Stan RV, Malik AB. Intersectin regulates fission and internalization of caveolae in endothelial cells. Mol Biol Cell. 2003;14(12):4997–5010.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Predescu SA, Predescu DN, Knezevic I, Klein IK, Malik AB. Intersectin-1 s regulates the mitochondrial apoptotic pathway in endothelial cells. J Biol Chem. 2007;282(23):17166–78.CrossRefPubMedGoogle Scholar
  34. Pucharcos C, Estivill X, de la Luna S. Intersectin 2, a new multimodular protein involved in clathrin-mediated endocytosis. FEBS Lett. 2000;478(1–2):43–51.CrossRefPubMedGoogle Scholar
  35. Quinn CC, Chen E, Kinjo TG, Kelly G, Bell AW, Elliott RC, et al. TUC-4b, a novel TUC family variant, regulates neurite outgrowth and associates with vesicles in the growth cone. J Neurosci. 2003;23(7):2815–23.CrossRefPubMedGoogle Scholar
  36. Rikhy R, Kumar V, Mittal R, Krishnan KS. Endophilin is critically required for synapse formation and function in Drosophila melanogaster. J Neurosci. 2002;22(17):7478–84.CrossRefPubMedGoogle Scholar
  37. Rodal AA, Motola-Barnes RN, Littleton JT. Nervous wreck and Cdc42 cooperate to regulate endocytic actin assembly during synaptic growth. J Neurosci. 2008;28(33):8316–25.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Rodriguez-Fraticelli AE, Vergarajauregui S, Eastburn DJ, Datta A, Alonso MA, Mostov K, et al. The Cdc42 GEF Intersectin 2 controls mitotic spindle orientation to form the lumen during epithelial morphogenesis. J Cell Biol. 2010;189(4):725–38.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Roos J, Kelly RB. Dap160, a neural-specific Eps15 homology and multiple SH3 domain-containing protein that interacts with Drosophila dynamin. J Biol Chem. 1998;273(30):19108–19.CrossRefPubMedGoogle Scholar
  40. Rose S, Malabarba MG, Krag C, Schultz A, Tsushima H, Di Fiore PP, et al. Caenorhabditis elegans intersectin: a synaptic protein regulating neurotransmission. Mol Biol Cell. 2007;18(12):5091–9.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Sengar AS, Wang W, Bishay J, Cohen S, Egan SE. The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15. EMBO J. 1999;18(5):1159–71.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Smith SM, Renden R, von Gersdorff H. Synaptic vesicle endocytosis: fast and slow modes of membrane retrieval. Trends Neurosci. 2008;31(11):559–68.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Sweeney ST, Davis GW. Unrestricted synaptic growth in spinster-a late endosomal protein implicated in TGF-beta-mediated synaptic growth regulation. Neuron. 2002;36(3):403–16.CrossRefPubMedGoogle Scholar
  44. Thomas S, Ritter B, Verbich D, Sanson C, Bourbonniere L, McKinney RA, et al. Intersectin regulates dendritic spine development and somatodendritic endocytosis but not synaptic vesicle recycling in hippocampal neurons. J Biol Chem. 2009;284(18):12410–9.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Verstreken P, Koh TW, Schulze KL, Zhai RG, Hiesinger PR, Zhou Y, et al. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron. 2003;40(4):733–48.CrossRefPubMedGoogle Scholar
  46. Wang JB, WJ W, Cerione RA. Cdc42 and Ras cooperate to mediate cellular transformation by intersectin-L. J Biol Chem. 2005;280(24):22883–91.CrossRefPubMedGoogle Scholar
  47. Wang W, Bouhours M, Gracheva EO, Liao EH, Xu K, Sengar AS, et al. ITSN-1 controls vesicle recycling at the neuromuscular junction and functions in parallel with DAB-1. Traffic. 2008;9(5):742–54.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Xie J, Vandenbroere I, Pirson I. SHIP2 associates with intersectin and recruits it to the plasma membrane in response to EGF. FEBS Lett. 2008;582(20):3011–7.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Yamabhai M, Hoffman NG, Hardison NL, McPherson PS, Castagnoli L, Cesareni G, et al. Intersectin, a novel adaptor protein with two Eps15 homology and five Src homology 3 domains. J Biol Chem. 1998;273(47):31401–7.CrossRefPubMedGoogle Scholar
  50. Yu Y, Chu PY, Bowser DN, Keating DJ, Dubach D, Harper I, et al. Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities. Hum Mol Genet. 2008;17(21):3281–90.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Ameet S. Sengar
    • 1
  • Michael W. Salter
    • 1
  • Sean E. Egan
    • 2
    Email author
  1. 1.Program in Neurosciences and Mental HealthThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Program in Developmental and Stem Cell BiologyThe Hospital for Sick ChildrenTorontoCanada