The N-terminal Coiled Coil Domain of the Cytohesin/ARNO Family of Guanine Nucleotide Exchange Factors Interacts with the Scaffolding Protein CASP

Cytohesin is a guanine nucleotide exchange factor that regulates members of the ADP-ribosylation factor (ARF) family of small GTPases. All of the members of the cytohesin family (including ARNO, ARNO3, and the newly characterized cytohesin-4) have a similar domain distribution consisting of a Sec7 homology domain, a pleckstrin homology domain, and an N-terminal coiled coil. In this study, we attempt to identify proteins that interact specifically with the coiled coil motif of cytohesin. Yeast two-hybrid screening of a B cell library using the cytohesin N terminus as bait, identified CASP, a scaffolding protein of previously unknown function, as a binding partner. CASP contains an internal coiled coil motif that is required for cytohesin binding both in vitro and in COS-1 cells. The specificity of the coiled coil of CASP is not restricted to cytohesin, however, because it is also capable of interacting with other members of the cytohesin/ARNO family, ARNO and ARNO3. In immunofluorescence experiments, CASP localizes to perinuclear tubulovesicular structures that are in close proximity to the Golgi. These structures remain relatively undisturbed when the cells are treated with brefeldin A. In epidermal growth factor-stimulated COS-1 cells overexpressing cytohesin and CASP, cytohesin recruits CASP to membrane ruffles, revealing a functional interaction between the two proteins. 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. Cytohesin is a guanine nucleotide exchange factor that regulates members of the ADP-ribosylation factor (ARF) family of small GTPases. All of the members of the cytohesin family (including ARNO, ARNO3, and the newly characterized cytohesin-4) have a similar domain distribution consisting of a Sec7 homology domain, a pleckstrin homology domain, and an N-terminal coiled coil. In this study, we attempt to identify proteins that interact specifically with the coiled coil motif of cytohesin. Yeast two-hybrid screening of a B cell library using the cytohesin N terminus as bait, identified CASP, a scaffolding protein of previously unknown function, as a binding partner. CASP contains an internal coiled coil motif that is required for cytohesin binding both in vitro and in COS-1 cells. The specificity of the coiled coil of CASP is not restricted to cytohesin, however, because it is also capable of interacting with other members of the cytohesin/ARNO family, ARNO and ARNO3. In immunofluorescence experiments, CASP localizes to perinuclear tubulovesicular structures that are in close proximity to the Golgi. These structures remain relatively undisturbed when the cells are treated with brefeldin A. In epidermal growth factor-stimulated COS-1 cells overexpressing cytohesin and CASP, cytohesin recruits CASP to membrane ruffles, revealing a functional interaction between the two proteins. 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. guanine nucleotide exchange factor pleckstrin homology brefeldin A endoplasmic reticulum amino acid(s) glutathioneS-transferase cytomegalovirus hemagglutinin phosphate-buffered saline epidermal growth factor ADP-ribosylation factor The cytohesin/ARNO family of guanine nucleotide exchange factors (GEFs),1 characterized by an N-terminal coiled coil, a Sec7 homology domain, and a C-terminal pleckstrin homology (PH) domain, have emerged as regulators of the ARF family of small GTPases (1Chardin P. Paris S. Antonny B. Robineau S. Beraud-Dufour S. Jackson C.L. Chabre M. Nature. 1996; 384: 481-484Crossref PubMed Scopus (409) Google Scholar, 2Meacci E. Tsai S.C. Adamik R. Moss J. Vaughan M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1745-1748Crossref PubMed Scopus (136) Google Scholar, 3Klarlund J.K. Rameh L.E. Cantley L.C. Buxton J.M. Holik J.J. Sakelis C. Patki V. Corvera S. Czech M.P. J. Biol. Chem. 1998; 273: 1859-1862Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). ARF GTPases are divided into three classes based on their gene structure. Class I ARFs (ARFs 1–3) are Golgi-associated GTPases regulating vesicle formation (4Stearns T. Willingham M.C. Botstein D. Kahn R.A. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 1238-1242Crossref PubMed Scopus (269) Google Scholar, 5Hosaka M. Toda K. Takatsu H. Torii S. Murakami K. Nakayama K. J. Biochem. (Tokyo). 1996; 120: 813-819Crossref PubMed Scopus (63) Google Scholar, 6Tsai S.C. Adamik R. Haun R.S. Moss J. Vaughan M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9272-9276Crossref PubMed Scopus (40) Google Scholar). Little is known about class II ARFs (ARFs 4 and 5), except that ARF5 may be involved in brefeldin A (BFA)-resistant Golgi/ER retrograde traffic (7Claude A. Zhao B.P. Kuziemsky C.E. Dahan S. Berger S.J. Yan J.P. Armold A.D. Sullivan E.M. Melancon P. J. Cell Biol. 1999; 146: 71-84Crossref PubMed Google Scholar). ARF6, the only member of class III ARFs, associates with cell membranes and is involved in endocytosis and actin rearrangements (8D'Souza Schorey C., Li, G. Colombo M.I. Stahl P.D. Science. 1995; 267: 1175-1178Crossref PubMed Scopus (374) Google Scholar, 9Schafer D.A. D'Souza-Schorey C. Cooper J.A. Traffic. 2000; 1: 892-903Crossref PubMed Scopus (7) Google Scholar, 10Radhakrishna H., Al- Awar O. Khachikian Z. Donaldson J.G. J. Cell Sci. 1999; 112: 855-866Crossref PubMed Google Scholar). The study of ARF function has been focusing primarily on the ER and Golgi where different anterograde and retrograde vesicle trafficking pathways occur. It is generally accepted that coat protein complex (COP) II-coated vesicles budding from the ER carry cargo proteins to the ER/Golgi intermediate compartment where they are replaced by coat protein complex (COP) I-coated vesicles (11Antonny B. Schekman R. Curr. Opin. Cell Biol. 2001; 13: 38-43Crossref Scopus (163) Google Scholar). Sar1 is the major small GTPase implicated in the formation of these vesicles (12Aridor M. Weissman J. Bannykh S. Nuoffer C. Balch W.E. J. Cell Biol. 1998; 141: 61-70Crossref PubMed Scopus (249) Google Scholar, 13Aridor M. Fish K.N. Bannykh S. Weissman J. Roberts T.H. Lippincott-Schwartz J. Balch W.E. J. Cell Biol. 2001; 152: 213-229Crossref PubMed Scopus (206) Google Scholar), whereas the ARFs control COPI- as well as clathrin-coated vesicle formation and traffic in and around the Golgi (14Allan B.B. Balch W.E. Science. 1999; 285: 63-66Crossref PubMed Scopus (107) Google Scholar, 15Drake M.T. Zhu Y Kornfeld S. Mol. Biol. Cell. 2000; 11: 3723-3736Crossref PubMed Scopus (55) Google Scholar, 16Zhu Y. Traub L.M. Kornfeld S. Mol. Biol. Cell. 1998; 9: 1323-1337Crossref PubMed Scopus (88) Google Scholar). The cytohesin/ARNO GEFs regulate ARFs through the Sec7 homology domain by facilitating a GDP/GTP exchange, converting inactive GDP-bound ARFs to their active GTP-bound state (1Chardin P. Paris S. Antonny B. Robineau S. Beraud-Dufour S. Jackson C.L. Chabre M. Nature. 1996; 384: 481-484Crossref PubMed Scopus (409) Google Scholar, 2Meacci E. Tsai S.C. Adamik R. Moss J. Vaughan M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1745-1748Crossref PubMed Scopus (136) Google Scholar, 3Klarlund J.K. Rameh L.E. Cantley L.C. Buxton J.M. Holik J.J. Sakelis C. Patki V. Corvera S. Czech M.P. J. Biol. Chem. 1998; 273: 1859-1862Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). There are currently four known members of the cytohesin/ARNO family. The first was originally cloned in our laboratory and was designated B2-1 (17Liu L. Pohajdak B. Biochim. Biophys. Acta. 1992; 1132: 75-78Crossref PubMed Scopus (64) Google Scholar). It was later renamed by others as cytohesin-1 (18Kolanus W. Nagel W. Schiller B. Zeitlmann L. Godar S. Stockinger H. Seed B. Cell. 1996; 86: 233-242Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar). ARNO is also known as cytohesin-2, and ARNO3 is the human homolog of mouse GRP1 (19Franco M. Boretto J. Robineau S. Monier S. Goud B. Chardin P. Chavrier P. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9926-9931Crossref PubMed Scopus (85) Google Scholar). Another member of the cytohesin/ARNO family, cytohesin-4, was recently identified in blood cells (20Ogasawara M. Kim S.C. Adamik R. Togawa A. Ferrans V.J. Takeda K. Kirby M. Moss J. Vaughan M. J. Biol. Chem. 2000; 275: 3221-3320Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). To simplify nomenclature, we will follow the designations published in GenBankTM: cytohesin-1, ARNO, ARNO3, and cytohesin-4. The specificity of cytohesin/ARNO members to the various ARFs appears to be mediated primarily by the Sec7 domain. All cytohesin/ARNO members activate ARF-1 (19Franco M. Boretto J. Robineau S. Monier S. Goud B. Chardin P. Chavrier P. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9926-9931Crossref PubMed Scopus (85) Google Scholar, 20Ogasawara M. Kim S.C. Adamik R. Togawa A. Ferrans V.J. Takeda K. Kirby M. Moss J. Vaughan M. J. Biol. Chem. 2000; 275: 3221-3320Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar), whereas cytohesin-1, ARNO, and ARNO3 (but not cytohesin-4) activate ARF6 (20Ogasawara M. Kim S.C. Adamik R. Togawa A. Ferrans V.J. Takeda K. Kirby M. Moss J. Vaughan M. J. Biol. Chem. 2000; 275: 3221-3320Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 21Frank S. Upender S. Hansen S.H. Casanova J.E. J. Biol. Chem. 1998; 273: 23-27Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 22Langille S.E. Patki V. Klarlund J.K. Buxton J.M. Holik J.J. Chawla A. Corvera S. Czech M.P. J. Biol. Chem. 1999; 274: 27099-27104Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). Cytohesin-1 can activate ARF3 (2Meacci E. Tsai S.C. Adamik R. Moss J. Vaughan M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1745-1748Crossref PubMed Scopus (136) Google Scholar, 23Pacheco-Rodriguez G. Meacci E. Vitale N. Moss J. Vaughan M. J. Biol. Chem. 1998; 273: 26543-26548Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), whereas both cytohesin-1 and -4 can activate ARF-5. All four members of the family are highly similar on a structural basis. In addition to the Sec7 homology domain, the C-terminal PH domain allows cytohesin/ARNO interactions with membranes by binding to various polyphosphoinositides (24Venkateswarlu K. Gunn-Moore F. Oatey P.B. Tavare J.M. Cullen P.J. Biochem. J. 1998; 335: 139-146Crossref PubMed Scopus (118) Google Scholar, 25Venkateswarlu K. Gunn-Moore F. Tavare J.M. Cullen P.J. J. Cell Sci. 1999; 112: 1957-1965PubMed Google Scholar, 26Klarlund J.K. Tsiaras W. Holik J.J. Chawla A. Czech M.P. J. Biol. Chem. 2000; 275: 32816-32821Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 27Macia E. Paris S. Chabre M. Biochemistry. 2000; 39: 5893-5901Crossref PubMed Scopus (57) Google Scholar). Although the PH domains of cytohesin-1 and ARNO seem to bind nonselectively to various phosphoinositides, ARNO3 shows increased affinity to phosphatidylinositol 3,4,5-trisphosphate, a product of phosphatidylinositol 3-kinase activation (26Klarlund J.K. Tsiaras W. Holik J.J. Chawla A. Czech M.P. J. Biol. Chem. 2000; 275: 32816-32821Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 28Lietzke S.E. Bose S. Cronin T. Klarlund J. Chawla A. Czech M.P. Lambright D.G. Mol. Cell. 2000; 6: 385-394Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar). Generally, whereas the PH domain anchors the cytohesin/ARNO GEFs to membrane structures, the Sec7 domain facilitates the function of ARF in vesicle formation. The N-terminal coiled coil motif, reminiscent of leucine zipper domains, is a signature domain of all the cytohesin/ARNO members and still the most elusive. Recently, we showed that this domain targets the cytohesin/ARNO proteins to the Golgi (29Lee S.Y. Pohajdak B. J. Cell Sci. 2000; 113: Google Scholar, S.Y. M. Pohajdak B. Cell 2000; PubMed Scopus (7) Google Scholar). The coiled coil motif most with at least one protein that contains a similar domain and facilitates the of that regulate vesicle formation. The only protein known to interact with the N terminus of a cytohesin/ARNO protein homolog of ARNO3, is a scaffolding protein of unknown function a coiled coil domain V.J. D. J.E. Hansen P. M.I. M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). we the interaction of cytohesin/ARNO cytohesin, with a scaffolding CASP, originally cloned in our laboratory from human B. B. L. Pohajdak B. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). CASP and a similar domain with an N-terminal domain, a coiled coil motif, and C-terminal domain of unknown A cytohesin for (29Lee S.Y. Pohajdak B. J. Cell Sci. 2000; 113: Google was in into of the from the domain A human B cell library into the of the activation domain and the for the two-hybrid from C. A for was in A for for and by the CASP for the coiled coil motif, of the and into the The for the coiled coil was and proteins a of the coiled coil domain in a similar using a CASP with an CASP with the and CASP for the coiled coil domain into a designated In these the CASP and the CASP coiled coil cloned in with and and was the control of the of CASP and CASP the of the coiled coil motif and CASP into in a similar for the CASP and and Cytohesin a was cloned into the from an and to the N of cytohesin, ARNO, and ARNO3, (29Lee S.Y. Pohajdak B. J. Cell Sci. 2000; 113: Google into a in with an and a the control of the COS-1 cells for by K. and in with and The was into cells using a Yeast on in at in the and protein was by of using Yeast the with of the human B cell on and and at for The a and for a and with to by using and cloned into the II and using an The using the at the for To cells the with for at The cells in with and the with for at The three in with and as a in with To of cells of the cytohesin, ARNO, and ARNO3 N-terminal with for at The cells in to with of The with and the proteins on the by in of and of with The in with and the proteins with of in was to by of with proteins with of in of saline with and for at The with saline with and to proteins by and COS-1 cells in the with of the CASP of and 4 of in the of and The cells in of saline with with and the by at for and with of and of at with for The with saline with and to CASP and proteins by using and COS-1 cells on in with of and 4 of of CASP also with of cytohesin in the the cells for in a and and with of for at and cells in in for with in and with at in with and in with at was from from a from and from and from Yeast two-hybrid screening based on the and using cytohesin as identified three of all three with the N terminus of cytohesin was in by and All three two of to CASP, a gene originally cloned in our laboratory from a human of B. B. L. Pohajdak B. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). The to a gene and was to be a binding of cytohesin. CASP and most of the in the The interacting CASP for a CASP protein that the terminus and the of the coiled coil domain The of coiled coil in both the and the proteins to that the interaction was mediated by these and to this interaction in vitro and in a cellular The N terminus of cytohesin a coiled coil motif that most with coiled coil domain. The of a domain in the CASP protein in to the interaction of cytohesin with the CASP coiled coil in to CASP protein in it a to proteins that specifically the coiled coil domain of CASP A and These proteins they they also the by the proteins to the the binding we of the CASP proteins a of the coiled coil. In addition to the of of the coiled coil, this also the of the N-terminal cytohesin to and to a was in E. and for interaction with the proteins. only be in vitro by CASP to when the coiled coil of CASP The of CASP on the other and to interact with to the of the interaction that we in vitro by COS-1 cells with and CASP coiled coil domain and for an interaction in COS-1 CASP in cells be with our as a of in CASP protein in cells. It was to CASP with a for by A was also to CASP in the of using on COS-1 to the showed affinity to COS-1 to and CASP using and was also to a for by using CASP with from COS-1 using interaction is specific to the coiled coil domain of CASP because the CASP the of the coiled coil domain as the CASP in the in vitro showed interaction with CASP was not with protein and the of of the proteins in COS-1 cells was by proteins from of the using All members of the cytohesin/ARNO family are characterized by an N-terminal coiled coil the binding specificity of CASP to the various members of this family of ARNO and ARNO3. proteins to the N of ARNO and ARNO3 and the coiled coil motif in E. and for their to interact with proteins in and capable of interacting with an CASP coiled coil domain not with the of the protein These interactions in COS-1 cells by with CASP CASP and with CASP not the with both and from COS-1 CASP shows specificity to the various members of the cytohesin/ARNO family in both our in vitro and COS-1 binding interaction with and is mediated by the coiled coil for ARNO and ARNO3 cloned from an and from a the control of the COS-1 cells with ARNO, ARNO3, and CASP as ARNO, ARNO3, CASP and CASP proteins by using of ARNO, ARNO3, CASP and CASP in COS-1 cells was by of proteins with by using ARNO and ARNO3 are with CASP and CASP are have previously that the cytohesin, ARNO, and ARNO3 to the Golgi through their coiled coil that CASP may be a Golgi protein because it with all three members of the cytohesin/ARNO family. of CASP in COS-1 cells shows a perinuclear that is of the Golgi. To our however, CASP not with the Golgi II it with the ER not It however, with the ER/Golgi intermediate was when COS-1 cells treated with the of both and CASP into similar structures the of II into the ER as J. B. U. P. G. 1997; PubMed Scopus Google Scholar, J. E. M. G. Nature. 2000; PubMed Scopus Google Scholar). The tubulovesicular structures in proximity the Golgi and the of CASP and in COS-1 cells. COS-1 cells with and and and the of both and CASP into and CASP and was with and The when COS-1 cells treated with with and Cytohesin localizes to the Golgi when at in COS-1 cells (29Lee S.Y. Pohajdak B. J. Cell Sci. 2000; 113: Google Scholar, S.Y. M. Pohajdak B. Cell 2000; PubMed Scopus (7) Google distribution when in and cells K. Gunn-Moore F. Tavare J.M. Cullen P.J. J. Cell Sci. 1999; 112: 1957-1965PubMed Google Scholar). cytohesin can be to and membranes by the stimuli. of GRP1 was by others in COS-1 cells with S.E. Patki V. Klarlund J.K. Buxton J.M. Holik J.J. Chawla A. Corvera S. Czech M.P. J. Biol. Chem. 1999; 274: 27099-27104Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). the of cytohesin in COS-1 cells and that cytohesin, to the membrane A and CASP and a of CASP a of the coiled coil domain, perinuclear that was by cytohesin was with CASP, however, the of both cytohesin and CASP to membrane In both CASP and cytohesin a distribution with membrane CASP perinuclear in these cells was as a of cytohesin CASP through the coiled of CASP to membrane in the of cytohesin is on the CASP coiled coil motif, because the to the CASP to membrane is mediated by cytohesin because CASP not to when of CASP and cytohesin in COS-1 cells with cytohesin and with for Cytohesin was with and and CASP and proteins with and and and and when Cytohesin was with a not a two-hybrid to identify proteins that specifically interact with the coiled coil domain in the N terminus of cytohesin. cytohesin amino as bait, we identified CASP as a binding partner. CASP was originally cloned in our laboratory from a cell suggest the of CASP in other cell as B and as well as a of and CASP contains at least two known protein interaction an N-terminal domain and a coiled coil The of a coiled coil in CASP to that the interaction is mediated by this In vitro binding with CASP proteins primarily the coiled coil motif and of the protein in the coiled coil motif is that this of CASP specifically with the coiled coil of cytohesin. interaction in COS-1 cells coiled coil of cytohesin, CASP, and coiled coil of CASP that the interaction is specifically mediated by the coiled coil CASP was identified by others as a protein by two screening of a cell library and was to as a protein In that however, the of cytohesin was as bait, and the protein for the interaction are the first to an interaction both in vitro and in a cellular as well as to identify the domains for this The specificity of the CASP coiled coil domain was by the interaction of CASP with other members of cytohesin/ARNO family, ARNO and All three members are with the Golgi of COS-1 cells (29Lee S.Y. Pohajdak B. J. Cell Sci. 2000; 113: Google and most specific in vesicle formation. CASP is capable of interacting with all three members of the family, at least in our There may be specificity with the various at a that by the that to be to an interaction by proteins from cell to the of functional CASP our suggest that CASP may regulate a of vesicle that at least one member of the cytohesin family in cells. The interaction of CASP with in COS-1 cells an of CASP with the Golgi showed the of CASP with Golgi with Golgi on the other showed that CASP was not with the Golgi. The only that was a well of the intermediate A. M. T. G. J. Cell Sci. PubMed Google Scholar). the of both CASP and into similar not tubulovesicular have that the of the Golgi and the of Golgi as II into the whereas other as and the in tubulovesicular structures J. E. M. G. Nature. 2000; PubMed Scopus Google Scholar). It appears that CASP is with a compartment that with the Golgi and with Golgi compartment may be of the ER/Golgi intermediate is from the The interaction of CASP with cytohesin and the of CASP and cytohesin proteins with different of the perinuclear most the of the function of The interaction of CASP and cytohesin at the Golgi may that remain to in COS-1 cells overexpressing CASP and cytohesin the functional interaction of the two proteins. the coiled coil interaction is for the The of CASP in the of cytohesin is mediated by the PH domain of cytohesin, a of cytohesin by others in cells K. Gunn-Moore F. Tavare J.M. Cullen P.J. J. Cell Sci. 1999; 112: 1957-1965PubMed Google Scholar). Cytohesin to membranes is similar to GRP1 and ARNO by other (24Venkateswarlu K. Gunn-Moore F. Oatey P.B. Tavare J.M. Cullen P.J. Biochem. J. 1998; 335: 139-146Crossref PubMed Scopus (118) Google Scholar, K. Oatey P.B. Tavare J.M. Cullen P.J. Curr. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google and is with the of all three proteins to activate ARF6 in vitro and membrane ARF6 in S. Upender S. Hansen S.H. Casanova J.E. J. Biol. Chem. 1998; 273: 23-27Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, K. Cullen P.J. Biochem. J. 2000; PubMed Scopus Google Scholar). CASP to to the most as a of the CASP with cytohesin The of CASP to cytohesin to the membrane in response to is because the interaction of cytohesin with CASP and membranes is mediated by two different the coiled coil and the PH domain, The of CASP and cytohesin at membranes that cytohesin is capable of CASP to the of in response to specific stimuli. CASP is not the only protein capable of interacting with cytohesin/ARNO proteins through their N-terminal coiled coil domain. scaffolding the only other known member of the CASP family, was recently cloned from a mouse library and to interact with both ARNO and GRP1 V.J. D. J.E. Hansen P. M.I. M. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). is by in and interaction with GRP1 at the cell The of to interact with cytohesin was because it is not in cells. The structural between CASP and and their of interacting with members of the cytohesin/ARNO family suggest that the family of scaffolding proteins a in vesicle formation at a of cellular CASP and are to be by cytohesin/ARNO members and may as scaffolding proteins to in other proteins to the of domains of CASP and the domain and the C-terminal domain, may also proteins to the of their function may proteins into a In the of CASP and are not because is only in response to and both CASP and In we identified the first protein to interact with the N-terminal coiled coil domain of cytohesin. The of CASP a for CASP in a cell of vesicle at the of the Golgi a by interacting with the cytohesin/ARNO and their are currently to the perinuclear compartment by CASP as well as the for this perinuclear CASP may a scaffolding protein that regulates a of vesicle formation and

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