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Gene Review

CYTH2  -  cytohesin 2

Homo sapiens

Synonyms: ARF exchange factor, ARF nucleotide-binding site opener, ARNO, CTS18, CTS18.1, ...
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Disease relevance of PSCD2

  • Murine gammaherpesvirus gammaHV68 is genetically and biologically related to human gammaherpesviruses and herpesvirus saimiri and has been reported to be associated with lymphoproliferative disease in mice (N. P. Sunil-Chandra, J. Arno, J. Fazakerley, and A. A. Nash, Am. J. Pathol. 145:818-826, 1994) [1].
  • Three other trial were designed as cross-over studies; the Intergroup Exemestane Study (IES) and the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8/German ARNO 95 trial compared a crossover from tamoxifen to an aromatase inhibitor versus continued tamoxifen in women who had completed 2 to 3 years of tamoxifen [2].
  • Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial [3].

High impact information on PSCD2

  • Structure of the guanine nucleotide exchange factor Sec7 domain of human arno and analysis of the interaction with ARF GTPase [4].
  • Here we characterized a smaller human protein (relative molecular mass 47K) named ARNO, which contains a central Sec7 domain that promotes guanine-nucleotide exchange on ARF1 [5].
  • This suggests that a regulatory component which is sensitive to brefeldin A associates with ARNO in vivo, possibly through the amino-terminal coiled-coil [5].
  • The a2-isoform is targeted to early endosomes, interacts with ARNO in an intra-endosomal acidification-dependent manner, and disruption of this interaction results in reversible inhibition of endocytosis [6].
  • The recruitment of the small GTPase Arf6 and ARNO from cytosol to endosomal membranes is driven by V-ATPase-dependent intra-endosomal acidification [6].

Biological context of PSCD2


Anatomical context of PSCD2

  • Furthermore, based on subcellular fractionation and immunolocalization experiments, we find that ARNO is localized to the plasma membrane in mammalian cells rather than the Golgi [11].
  • When expressed in murine 3T3 L1 adipocytes, ARNO tagged using green fluorescent protein (GFP) is localised exclusively in the cytoplasm [12].
  • Overexpression of ARP-Q79L, but not of ARP-T31N, in COS-7 cells reduced the fluorescence from co-expressed green fluorescent protein fused with mSec7-1/cytohesin or mSec7-2/ARNO in plasma membranes as detected by deconvolution microscopy [13].
  • ARNO but not cytohesin-1 translocation is phosphatidylinositol 3-kinase-dependent in HL-60 cells [14].
  • ARNO mutants: DeltaCC-ARNO and CC-ARNO were partially translocated to the membranes while DeltaPH-ARNO and PH-ARNO could not be translocated to the membranes [15].

Associations of PSCD2 with chemical compounds


Physical interactions of PSCD2


Enzymatic interactions of PSCD2


Co-localisations of PSCD2


Regulatory relationships of PSCD2

  • We report here that in vitro ARNO can stimulate nucleotide exchange on both ARF1 and ARF6 [11].
  • Our data strongly suggest that ARNO binds PIP3 in vivo and that this interaction causes a translocation of ARNO to the plasma membrane where it might activate ARF6 and regulate subsequent plasma membrane cycling events [12].
  • Here, we show that ARNO is expressed in HL-60 cells and established that granulocytic differentiation induced with Me2SO stimulated cytohesin-1 but not ARNO expression [14].
  • Overexpression of wild type ARNO significantly increased insulin-stimulated PLD activity, and mutations in the Sec7 and PH domains, or deletion of the PH or CC domains inhibited the effects of insulin [15].
  • In contrast, a similar mutant of the Rac GEF beta-PIX fails to inhibit ARNO-induced Rac activation or motility [23].

Other interactions of PSCD2

  • In this system, ARD1-GDP interacted well with cytohesin-1 but very poorly with cytohesin-2 [24].
  • It is therefore likely that ARNO functions in plasma membrane events by modulating the activity of ARF6 in vivo [11].
  • In agreement, cytohesin-1, but not cytohesin-2, markedly accelerated [(35)S]guanosine 5'-3-O-(thio)triphosphate binding to ARD1 [24].
  • These observations collectively suggest that CASP is a scaffolding protein that facilitates the function of at least one member of the cytohesin/ARNO family in response to specific cellular stimuli [19].
  • Here, we report crystal structures for dual specificity variants of the Grp1 and ARNO PH domains in either the unliganded form or in complex with the head groups of PtdIns(4,5)P(2) and PtdIns(3,4,5)P(3) [25].

Analytical, diagnostic and therapeutic context of PSCD2


  1. Murine gammaherpesvirus 68 infection is associated with lymphoproliferative disease and lymphoma in BALB beta2 microglobulin-deficient mice. Tarakanova, V.L., Suarez, F., Tibbetts, S.A., Jacoby, M.A., Weck, K.E., Hess, J.L., Speck, S.H., Virgin, H.W. J. Virol. (2005) [Pubmed]
  2. Adjuvant therapy with aromatase inhibitors for postmenopausal women with early breast cancer: evidence and ongoing controversy. Wheler, J., Johnson, M., Seidman, A. Semin. Oncol. (2006) [Pubmed]
  3. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Jakesz, R., Jonat, W., Gnant, M., Mittlboeck, M., Greil, R., Tausch, C., Hilfrich, J., Kwasny, W., Menzel, C., Samonigg, H., Seifert, M., Gademann, G., Kaufmann, M., Wolfgang, J. Lancet (2005) [Pubmed]
  4. Structure of the guanine nucleotide exchange factor Sec7 domain of human arno and analysis of the interaction with ARF GTPase. Mossessova, E., Gulbis, J.M., Goldberg, J. Cell (1998) [Pubmed]
  5. A human exchange factor for ARF contains Sec7- and pleckstrin-homology domains. Chardin, P., Paris, S., Antonny, B., Robineau, S., Béraud-Dufour, S., Jackson, C.L., Chabre, M. Nature (1996) [Pubmed]
  6. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Hurtado-Lorenzo, A., Skinner, M., El Annan, J., Futai, M., Sun-Wada, G.H., Bourgoin, S., Casanova, J., Wildeman, A., Bechoua, S., Ausiello, D.A., Brown, D., Marshansky, V. Nat. Cell Biol. (2006) [Pubmed]
  7. Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2. Buchet-Poyau, K., Mehenni, H., Radhakrishna, U., Antonarakis, S.E. Cytogenet. Genome Res. (2002) [Pubmed]
  8. ARNO3, a Sec7-domain guanine nucleotide exchange factor for ADP ribosylation factor 1, is involved in the control of Golgi structure and function. Franco, M., Boretto, J., Robineau, S., Monier, S., Goud, B., Chardin, P., Chavrier, P. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. Discriminatory aptamer reveals serum response element transcription regulated by cytohesin-2. Theis, M.G., Knorre, A., Kellersch, B., Moelleken, J., Wieland, F., Kolanus, W., Famulok, M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Interaction protein for cytohesin exchange factors 1 (IPCEF1) binds cytohesin 2 and modifies its activity. Venkateswarlu, K. J. Biol. Chem. (2003) [Pubmed]
  11. ARNO is a guanine nucleotide exchange factor for ADP-ribosylation factor 6. Frank, S., Upender, S., Hansen, S.H., Casanova, J.E. J. Biol. Chem. (1998) [Pubmed]
  12. Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase. Venkateswarlu, K., Oatey, P.B., Tavaré, J.M., Cullen, P.J. Curr. Biol. (1998) [Pubmed]
  13. The ADP-ribosylation factor (ARF)-related GTPase ARF-related protein binds to the ARF-specific guanine nucleotide exchange factor cytohesin and inhibits the ARF-dependent activation of phospholipase D. Schürmann, A., Schmidt, M., Asmus, M., Bayer, S., Fliegert, F., Koling, S., Massmann, S., Schilf, C., Subauste, M.C., Voss, M., Jakobs, K.H., Joost, H.G. J. Biol. Chem. (1999) [Pubmed]
  14. ARNO but not cytohesin-1 translocation is phosphatidylinositol 3-kinase-dependent in HL-60 cells. Bourgoin, S.G., Houle, M.G., Singh, I.N., Harbour, D., Gagnon, S., Morris, A.J., Brindley, D.N. J. Leukoc. Biol. (2002) [Pubmed]
  15. The guanine nucleotide exchange factor ARNO mediates the activation of ARF and phospholipase D by insulin. Li, H.S., Shome, K., Rojas, R., Rizzo, M.A., Vasudevan, C., Fluharty, E., Santy, L.C., Casanova, J.E., Romero, G. BMC Cell Biol. (2003) [Pubmed]
  16. A Sec7-related protein in Paramecium. Nair, S., Guerra, C., Satir, P. FASEB J. (1999) [Pubmed]
  17. Role of protein-phospholipid interactions in the activation of ARF1 by the guanine nucleotide exchange factor Arno. Paris, S., Béraud-Dufour, S., Robineau, S., Bigay, J., Antonny, B., Chabre, M., Chardin, P. J. Biol. Chem. (1997) [Pubmed]
  18. Distinct polyphosphoinositide binding selectivities for pleckstrin homology domains of GRP1-like proteins based on diglycine versus triglycine motifs. Klarlund, J.K., Tsiaras, W., Holik, J.J., Chawla, A., Czech, M.P. J. Biol. Chem. (2000) [Pubmed]
  19. The N-terminal coiled coil domain of the cytohesin/ARNO family of guanine nucleotide exchange factors interacts with the scaffolding protein CASP. Mansour, M., Lee, S.Y., Pohajdak, B. J. Biol. Chem. (2002) [Pubmed]
  20. beta-Arrestin-mediated ADP-ribosylation factor 6 activation and beta 2-adrenergic receptor endocytosis. Claing, A., Chen, W., Miller, W.E., Vitale, N., Moss, J., Premont, R.T., Lefkowitz, R.J. J. Biol. Chem. (2001) [Pubmed]
  21. A glutamic finger in the guanine nucleotide exchange factor ARNO displaces Mg2+ and the beta-phosphate to destabilize GDP on ARF1. Béraud-Dufour, S., Robineau, S., Chardin, P., Paris, S., Chabre, M., Cherfils, J., Antonny, B. EMBO J. (1998) [Pubmed]
  22. Remodeling of the actin cytoskeleton is coordinately regulated by protein kinase C and the ADP-ribosylation factor nucleotide exchange factor ARNO. Frank, S.R., Hatfield, J.C., Casanova, J.E. Mol. Biol. Cell (1998) [Pubmed]
  23. The DOCK180/Elmo complex couples ARNO-mediated Arf6 activation to the downstream activation of Rac1. Santy, L.C., Ravichandran, K.S., Casanova, J.E. Curr. Biol. (2005) [Pubmed]
  24. Specific functional interaction of human cytohesin-1 and ADP-ribosylation factor domain protein (ARD1). Vitale, N., Pacheco-Rodriguez, G., Ferrans, V.J., Riemenschneider, W., Moss, J., Vaughan, M. J. Biol. Chem. (2000) [Pubmed]
  25. Structural determinants of phosphoinositide selectivity in splice variants of Grp1 family PH domains. Cronin, T.C., DiNitto, J.P., Czech, M.P., Lambright, D.G. EMBO J. (2004) [Pubmed]
  26. Identification of a plasma membrane-associated guanine nucleotide exchange factor for ARF6 in chromaffin cells. Possible role in the regulated exocytotic pathway. Caumont, A.S., Vitale, N., Gensse, M., Galas, M.C., Casanova, J.E., Bader, M.F. J. Biol. Chem. (2000) [Pubmed]
  27. Overexpression of the ARF1 exchange factor ARNO inhibits the early secretory pathway and causes the disassembly of the Golgi complex. Monier, S., Chardin, P., Robineau, S., Goud, B. J. Cell. Sci. (1998) [Pubmed]
  28. Characterization of cytohesin-1 monoclonal antibodies: expression in neutrophils and during granulocytic maturation of HL-60 cells. Garceau, V., Houle, M.G., Chouinard, F., Gagnon, S., Harbour, D., Naccache, P.H., Bourgoin, S.G. J. Immunol. Methods (2001) [Pubmed]
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