Biopolym. Cell. 2013; 29(3):244-251.
Reviews
ITSN protein family: regulation of diversity, role in signalling and pathology
1Tsyba L. O., 1Dergai M. V., 1Skrypkina I. Ya., 1Nikolaienko O. V., 1Dergai O. V., 1Kropyvko S. V., 1Novokhatska O. V., 1Morderer D. Ye., 1Gryaznova T. A., 1Gubar O. S., 1Rynditch A. V.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680

Abstract

Adaptor/scaffold proteins of the intersectin (ITSN) family are important components of endocytic and signalling complexes. They coordinate trafficking events with actin cytoskeleton rearrangements and modulate the activity of a variety of signalling pathways. In this review, we present our results as a part of recent findings on the function of ITSNs, the role of alternative splicing in the generation of ITSN1 diversity and the potential relevance of ITSNs for neurodegenerative diseases, cancer.
Keywords: adaptor/scaffold proteins, intersectin family, alternative splicing, endocytosis

References

[1] Zeke A., Lukacs M., Lim W. A., Remenyi A. Scaffolds: interaction platforms for cellular signalling circuits Trends Cell Biol 2009 19, N 8:364–374.
[2] Shaw A. S., Filbert E. L. Scaffold proteins and immune-cell signalling Nat. Rev. Immunol 2009 9, N 1:47–56.
[3] Tsyba L., Nikolaienko O., Dergai O., Dergai M., Novokhatska O., Skrypkina I., Rynditch A. Intersectin multidomain adaptor proteins: regulation of functional diversity Gene 2011 473, N 2:67–75.
[4] O'Bryan J. P. Intersecting pathways in cell biology Sci. Signal 2010 3, N 152 re10.
[5] Hunter M. P., Nelson M., Kurzer M., Wang X., Kryscio R. J., Head E., Pinna G., O'Bryan J. P. Intersectin 1 contributes to phenotypes in vivo: implications for Down Syndrome Neuroreport 2011 22, N 15:767–772.
[6] Wilmot B., McWeeney S. K., Nixon R. R., Montine T. J., Laut J., Harrington C. A., Kaye J. A., Kramer P. L. Translational gene mapping of cognitive decline Neurobiol. Aging 2008 29, N 4 P. 524–541.
[7] Keating D. J., Chen C., Pritchard M. A. Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN 1 Ageing Res. Rev 2006 5, N 4 P. 388–401.
[8] Guipponi M., Scott H. S., Chen H., Schebesta A., Rossier C., Antonarakis S. E. Two isoforms of human intersectin (ITSN) protein are produced by brain-specific alternative splicing in a stop codon Genomics 1998 53, N 3:369–376.
[9] Pucharcos C., Casas C., Nadal M., Estivill X., de la Luna S. The human intersectin genes and their spliced variants are differentially expressed Biochim. Biophys. Acta 2001 1521, N 1–3:1–11.
[10] Hussain N. K., Jenna S., Glogauer M., Quinn C. C., Wasiak S., Guipponi M., Antonarakis S. E., Kay B. K., Stossel T. P., Lamarche-Vane N., McPherson P. S. Endocytic protein intersectin-1 regulates actin assembly via Cdc42 and N-WASP Nat. Cell. Biol 2001 3, N 10:927–932.
[11] Novokhatska O., Dergai M., Houssin N., Tsyba L., Moreau J., Rynditch A. Intersectin 2 nucleotide exchange factor regulates Cdc42 activity during Xenopus early development Biochem. Biophys. Res. Commun 2011 408, N 4:663–668.
[12] Rodriguez-Fraticelli A. E., Vergarajauregui S., Eastburn D. J., Datta A., Alonso M. A., Mostov K., Martin-Belmonte F. The Cdc42 GEF Intersectin 2 controls mitotic spindle orientation to form the lumen during epithelial morphogenesis J. Cell. Biol 2010 189, N 4:725–738.
[13] Nishimura T., Yamaguchi T., Tokunaga A., Hara A., Hamaguchi T., Kato K., Iwamatsu A., Okano H., Kaibuchi K. Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2 Mol. Biol. Cell–2006 17, N 3:1273–1285.
[14] Thomas S., Ritter B., Verbich D., Sanson C., Bourbonniere L., McKinney R. A., McPherson P. S. Intersectin regulates dendritic spine development and somatodendritic endocytosis but not synaptic vesicle recycling in hippocampal neurons J. Biol. Chem 2009 284, N 18:12410–12419.
[15] Sengar A. S., Wang W., Bishay J., Cohen S., Egan S. E. The EH and SH3 domain Ese proteins regulate endocytosis by linking to dynamin and Eps15 EMBO J 1999 18, N 5:1159–1171.
[16] Okamoto M., Schoch S., Sudhof T. C. EHSH1/intersectin, a protein that contains EH and SH3 domains and binds to dynamin and SNAP-25 J. Biol. Chem 1999 274, N 26:18446–18454.
[17] Yamabhai M., Hoffman N. G., Hardison N. L., McPherson P. S., Castagnoli L., Cesareni G., Kay B. K. Intersectin, a novel adaptor protein with two Eps15 homology and five Src homology 3 domains J. Biol. Chem 1998 273, N 47:31401–31407.
[18] Pechstein A., Bacetic J., Vahedi-Faridi A., Gromova K., Sundborger A., Tomlin N., Krainer G., Vorontsova O., Schafer J. G., Owe S. G., Cousin M. A., Saenger W., Shupliakov O., Haucke V. Regulation of synaptic vesicle recycling by complex formation between intersectin 1 and the clathrin adaptor complex AP2 Proc. Natl Acad. Sci. USA–2010 107, N 9:4206–4211.
[19] Dergai O., Novokhatska O., Dergai M., Skrypkina I., Tsyba L., Moreau J., Rynditch A. Intersectin 1 forms complexes with SGIP1 and Reps1 in clathrin-coated pits Biochem. Biophys. Res. Commun 2010 402, N 2:408–413.
[20] Koh T.W., Verstreken P., Bellen H. J. Dap160/intersectin acts as a stabilizing scaffold required for synaptic development and vesicle endocytosis Neuron 2004 43, N 2:193–205.
[21] Marie B., Sweeney S. T., Poskanzer K. E., Roos J., Kelly R. B., Davis G. W. Dap160/intersectin scaffolds the periactive zone to achieve highfidelity endocytosis and normal synaptic growth Neuron 2004 43, N 2:207–219.
[22] Yu Y., Chu P. Y., Bowser D. N., Keating D. J., Dubach D., Harper I., Tkalcevic J., Finkelstein D. I., Pritchard M. A. Mice deficient for the chromosome 21 ortholog ItsN 1 exhibit vesicletrafficking abnormalities Hum. Mol. Genet 2008 18, N 2 P. 3281–3290.
[23] Henne W. M., Boucrot E., Meinecke M., Evergren E., Vallis Y., Mittal R., McMahon H. T. FCHo proteins are nucleators of clathrin-mediated endocytosis Science 2010 328, N 5983 P. 1281–1284.
[24] Malacombe M., Ceridono M., Calco V., Chasserot-Golaz S., McPherson P. S., Bader M. F., Gasman S. Intersectin-1L nucleotide exchange factor regulates secretory granule exocytosis by activating Cdc42 EMBO J 2006 25, N 15:3494–3503.
[25] Momboisse F., Ory S., Ceridono M., Calco V., Vitale N., Bader M. F., Gasman S. The Rho guanine nucleotide exchange factors Intersectin 1L and b-Pix control calcium-regulated exocytosis in neuroendocrine PC12 cells Cell Mol. Neurobiol 2010 30, N 8:1327–1333.
[26] Sorkin A., Goh L. K. Endocytosis and intracellular trafficking of ErbBs Exp. Cell Res 2009 315, N 4:683–696.
[27] O'Bryan J. P., Mohney R. P., Oldham C. E. Mitogenesis and endocytosis: what's at the INTERSECTIoN? Oncogene 2001 20, N 44:6300–6308.
[28] McPherson P. S., Kay B. K., Hussain N. K. Signaling on the endocytic pathway Traffic 2001 2, N 6:375–384.
[29] Chen P. H., Chien F. C., Lee S. P., Chan W. E., Lin I. H., Liu C. S., Lee F. J., Lai J. S., Chen P., Yang-Yen H. F., Yen J. J. Identification of a novel function of the clathrin-coated structure at the plasma membrane in facilitating GM-CSF receptor-mediated activation of JAK2 Cell Cycle 2012 11, N 19:3611–3626.
[30] Martin N. P., Mohney R. P., Dunn S., Das M., Scappini E., O'Bryan J. P. Intersectin regulates epidermal growth factor receptor endocytosis, ubiquitylation, and signaling Mol. Pharmacol 2006 70, N5:1643–1653.
[31] Nikolaienko O. V., Skrypkina I. Ya., Tsyba L. O., Drobot L. B., Rynditch A.V. ITSN 1 and Ruk/CIN85 colocalized to clathrincoated pits in MCF-7 cells Biopolym. Cell 2009 25, N 5 P. 424–427.
[32] Nikolaienko O. V., Skrypkina I. Ya, Dergay O. V., Matskova L., Tsyba L. O., Dergay M. V., Kropivko S. V., Winberg G., Rynditch A. V. Cbl family proteins are new binding partners of intersectin 1 Factors of experimental evolution of organisms Kiev: Logos, 2006–Vol. 3:122–127.
[33] Okur M. N., Ooi J., Fong C. W., Martinez N., Garcia-Dominguez C., Rojas J. M., Guy G., O'Bryana J. P. Intersectin 1 enhances Cbl ubiquitylation of epidermal growth factor receptor through regulation of Sprouty2-Cbl interaction Mol. Cell. Biol 2012 32, N 4:817–825.
[34] Novokhatska O. V., Skrypkina I. Ya., Dergai M. V., Tsyba L. O., Rynditch A. V. RTK signaling regulator SPRY2 associates with endocytic adaptor ITSN 1 in vivo Biopolym. Cell 2012 28, N 4:314–316.
[35] Nikolaienko O., Skrypkina I., Tsyba L., Fedyshyn Y., Morderer D., Buchman V., de la Luna S., Drobot L., Rynditch A. Intersectin 1 forms a complex with adaptor protein Ruk/CIN85 in vivo independently of epidermal growth factor stimulation Cell. Signal 2009 21, N 5:753–759.
[36] Teckchandani A., Mulkearns E. E., Randolph T. W., Toida N., Cooper J. A. The clathrin adaptor Dab2 recruits EH domain scaffold proteins to regulate integrin b1 endocytosis mutations Mol. Biol. Cell 2012 23, N 15:2905–2916.
[37] Predescu S. A., Predescu D. N., Knezevic I., Klein I. K., Malik A. B. Intersectin-1s regulates the mitochondrial apoptotic pathway in endothelial cells J. Biol. Chem 2007 282, N23:17166– 17178.
[38] Bardita C., Predescu D.N, Justice M. J., Petrache I., Predescu S. In vivo knockdown of intersectin-1s alters endothelial cell phenotype and causes microvascular remodeling in the mouse lungs Apoptosis 2013 18, N 1:57–76.
[39] Das M., Scappini E.,Martin N. P.,Wong K. A., Dunn S., Chen Y. J., Miller S. L., Domin J., O'Bryan J. P. Regulation of neuron survival through an intersectin-phosphoinositide 3'-kinase C2betaAKT pathway Moll. Cell. Biol 2007 27, N 22:7906–7917.
[40] Wong K. A., Wilson J., Russo A., Wang L., Okur M. N., Wang X., Martin N. P., Scappini E., Carnegie G. K., O'Bryan J. P. Intersectin (ITSN) family of scaffolds function as molecular hubs in protein interaction networks PLoS One 2012 7, N 4 e36023.
[41] Tsyba L., Skrypkina I., Rynditch A., Nikolaienko O., Ferenets G., Fortna A., Gardiner K. Alternative splicing of mammalian Intersectin 1: domain associations and tissue specificities Genomics 2004 84, N 1:106–113.
[42] Kropyvko S., Gerasymchuk D., Skrypkina I., Dergai M., Dergai O., Nikolaienko O., Rynditch A., Tsyba L. Structural diversity and differential expression of novel human intersectin 1 isoforms Mol. Biol. Rep 2010 37, N 6:2789–2796.
[43] Tsyba L., Gryaznova T., Dergai O., Dergai M., Skrypkina I., Kropyvko S., Boldyryev O., Nikolaienko O., Novokhatska O., Rynditch A. Alternative splicing affecting the SH3A domain controls the binding properties of intersectin 1 in neurons Biochem. Biophys. Res. Commun 2008 372, N 4:929–934.
[44] Dergai M., Skrypkina I., Dergai O., Tsyba L., Novokhatska O., Filonenko V., Drobot L., Rynditch A. Identification and characterization of a novel mammalian isoform of the endocytic adaptor ITSN 1 Gene 2011 485, N 2:120–129.
[45] Dergai M., Tsyba L., Dergai O., Zlatskii I., Skrypkina I., Kovalenko V., Rynditch A. Microexon-based regulation of ITSN 1 and Src SH3 domains specificity relies on introduction of charged amino acids into the interaction interface Biochem. Biophys. Res. Commun 2010 399, N 2:307–312.
[46] McGlincy N. J., Smith C. W. Alternative splicing resulting in nonsense-mediated mRNA decay: what is the meaning of nonsense? Cell 2008 33, N 8:385–393.
[47] Kropyvko S. V., Tsyba L. O., Skrypkina I. Ya., Rynditch A. V. Identification and functional analysis of an alternative promoter of human intersectin 1 gene Biopolym. Cell 2010 26, N 2 P. 115–120.
[48] Pucharcos C., Fuentes J. J., Casas C., de la Luna S., Alcantara S., Arbones M. L., Soriano E., Estivill X., Pritchard M. Alu-splice cloning of human Intersectin (ITSN), a putative multivalent binding protein expressed in proliferating and differentiating neurons and overexpressed in Down syndrome Eur. J. Hum. Genet 1999 7, N 6:704–712.
[49] Skrypkina I., Tsyba L. O., Nikolaienko O. V., Kropivko S. V., Sopko N. I., Nikitchina T. V., Gordienko I. Yu., Rynditch A. V. Expression of intersectin 1 transcription isoforms in normal and Down syndrome tissues Bull. Gov. Found. Fund. Invest. of the Ukraine 2005:7–22.
[50] Scappini E., Koh T. W., Martin N. P., O'Bryan J. P. Intersectin enhances huntingtin aggregation and neurodegeneration through activation of c-Jun-NH2-terminal kinase (JNK) Hum. Mol. Genet 2007 16, N 15:1862–1871.
[51] Morderer D., Nikolaienko O., Skrypkina I., Cherkas V., Tsyba L., Belan P., Rynditch A. Endocytic adaptor protein intersectin 1 forms a complex with microtubule stabilizer STOP in neurons Gene 2012 505, N 2:360–364.
[52] Andrieux A., Salin P. A., Vernet M., Kujala P., Baratier J., GoryFaure S., Bosc C., Pointu H., Proietto D., Schweitzer A., Denarier E., Klumperman J., Job D. The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders Genes Dev 2002 16, N 18:2350–2364.
[53] Alto N. M., Orth K. Subversion of cell signaling by pathogens Cold Spring Harb. Perspect. Biol 2012 4, N 9 a006114.
[54] Dergai O., Dergai M., Skrypkina I., Matskova L., Tsyba L., Gudkova D., Rynditch A. The LMP2A protein of Epstein-Barr virus regulates phosphorylation of ITSN 1 and Shb adaptors by tyrosine kinases Cell. Signal 2013 25, N 1:33–40.
[55] Ma Y., Wang B., Li W., Ying G., Fu L., Niu R., Gu F. Reduction of intersectiN 1-s induced apoptosis of human glioblastoma cells Brain Res 2010 1351:222–228.
[56] Ma Y., Wang B., Li W., Liu X., Wang J., Ding T., Zhang J., Ying G., Fu L., Gu F. Intersectin 1-s is involved in migration and invasion of human glioma cells J. Neurosci. Res 2011 89, N 7 P. 1079–1090.
[57] Russo A., O'Bryan J. P. Intersectin 1 is required for neuroblastoma tumorigenesis Oncogene 2012 31, N 46:4828–4834.
[58] Specht K., Harbeck N., Smida J., Annecke K., Reich U., Naehrig J., Langer R., Mages J., Busch R., Kruse E., Klein-Hitpass L., Schmitt M., Kiechle M., Hoefler H. Expression profiling identifies genes that predict recurrence of breast cancer after adjuvant CMF-based chemotherapy Breast Cancer Res. Treat 2009 118, N 1:45–56.
[59] Kriachok I. A., Syvak L. A., Gubareva G. O., Lialkin S. A., Maidanevych N. M., Klimanov M. Yu., Askolskiy A. V., Kasap N. V., Smolanka I. I., Graboviy O. M., Tsyba L. O., Novokhatska O. V., Kropyvko S. V., Rynditch A. V. Role of intersectin 2 in prognosis of breast cancer Clinichna oncolohia (Ukraine) 2012 4, N 8 P. 158–160.