Identification of a Novel Inhibitory Actin-capping Protein Binding Motif in CD2-associated Protein

CD2-associated protein (CD2AP) is a scaffold molecule that plays a critical role in the maintenance of the kidney filtration barrier. Little, however, is understood about its mechanism of function. We used mass spectrometry to identify CD2AP-interacting proteins. Many of the proteins that we identified suggest a role for CD2AP in endocytosis and actin regulation. To address the role of CD2AP in regulation of the actin cytoskeleton, we focused on characterizing the interaction of CD2AP with actin-capping protein CP. We identified a novel binding motif LXHXTXXRPK(X)6P present in CD2AP that is also found in its homolog Cin85 and other capping protein-associated proteins such as CARMIL and CKIP-1. CD2AP inhibits the function of capping protein in vitro. Therefore, our results support a role of CD2AP in the regulation of the actin cytoskeleton. CD2-associated protein (CD2AP) is a scaffold molecule that plays a critical role in the maintenance of the kidney filtration barrier. Little, however, is understood about its mechanism of function. We used mass spectrometry to identify CD2AP-interacting proteins. Many of the proteins that we identified suggest a role for CD2AP in endocytosis and actin regulation. To address the role of CD2AP in regulation of the actin cytoskeleton, we focused on characterizing the interaction of CD2AP with actin-capping protein CP. We identified a novel binding motif LXHXTXXRPK(X)6P present in CD2AP that is also found in its homolog Cin85 and other capping protein-associated proteins such as CARMIL and CKIP-1. CD2AP inhibits the function of capping protein in vitro. Therefore, our results support a role of CD2AP in the regulation of the actin cytoskeleton. CD2-associated protein (CD2AP) 2The abbreviations used are: CD2AP, CD2-associated protein; GST, glutathione S-transferase; SH, Src homology; HEK, human embryonic kidney; HPLC, high pressure liquid chromatography; Fmoc, N-(9-fluorenyl)methoxycarbonyl; SPR, surface plasmon resonance. 2The abbreviations used are: CD2AP, CD2-associated protein; GST, glutathione S-transferase; SH, Src homology; HEK, human embryonic kidney; HPLC, high pressure liquid chromatography; Fmoc, N-(9-fluorenyl)methoxycarbonyl; SPR, surface plasmon resonance. is a 70-kDa protein that was originally cloned as a protein that interacts with the cytoplasmic tail of CD2, a T lymphocyte and natural killer cell transmembrane protein (1Dustin M.L. Olszowy M.W. Holdorf A.D. Li J. Bromley S. Desai N. Widder P. Rosenberger F. van der Merwe P.A. Allen P.M. Shaw A.S. Cell. 1998; 94: 667-677Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar). It is composed of three Src homology 3 (SH3) domains at the NH2 terminus followed by proline-rich sequences and a coiled-coil domain at the extreme COOH terminus. It is expressed in all tissues except brain. Interestingly, CD2AP-deficient animals die of renal failure ∼6 weeks of age (2Shih N.Y. Li J. Karpitskii V. Nguyen A. Dustin M.L. Kanagawa O. Miner J.H. Shaw A.S. Science. 1999; 286: 312-315Crossref PubMed Scopus (694) Google Scholar). In the kidney, CD2AP is highly expressed in the glomerular epithelial cell, and it is implicated to play a role in a specialized cell junction known as a slit diaphragm (3Shih N.Y. Li J. Cotran R. Mundel P. Miner J.H. Shaw A.S. Am. J. Pathol. 2001; 159: 2303-2308Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar). A homolog of CD2AP, Cin85, was cloned as an interacting protein with the E3 ubiquitin ligase c-cbl (4Take H. Watanabe S. Takeda K. Yu Z.X. Iwata N. Kajigaya S. Biochem. Biophys. Res. Commun. 2000; 268: 321-328Crossref PubMed Scopus (137) Google Scholar) and as an inhibitor of phosphatidylinositol 3-kinase (5Gout I. Middleton G. Adu J. Ninkina N.N. Drobot L.B. Filonenko V. Matsuka G. Davies A.M. Waterfield M. Buchman V.L. EMBO J. 2000; 19: 4015-4025Crossref PubMed Scopus (121) Google Scholar). Recently, several endocytic and actin-associated molecules have been reported to interact with CD2AP and Cin85. Some proteins have been demonstrated to interact with both CD2AP and Cin85, whereas others have only been shown to bind one or the other. CD2AP has been shown to play a role in vesicular trafficking because of interactions with c-cbl and an active form of Rab4 (6Cormont M. Meton I. Mari M. Monzo P. Keslair F. Gaskin C. McGraw T.E. Le March-Brustel Y. Traffic. 2003; 4: 97-112Crossref PubMed Scopus (112) Google Scholar). Cin85 has also been shown to bind to molecules involved in endocytosis, such as endophilin, synaptojanin 2B1, and SHIP-1 and the clathrin scaffold HIP1R (7Kowanetz K. Husnjak K. Holler D. Kowanetz M. Soubeyran P. Hirsch D. Schmidt M.H. Pavelic K. De Camilli P. Randazzo P.A. Dikic I. Mol. Biol. Cell. 2004; 15: 3155-3166Crossref PubMed Scopus (102) Google Scholar, 8Soubeyran P. Kowanetz K. Szymkiewicz I. Langdon W.Y. Dikic I. Nature. 2002; 416: 183-187Crossref PubMed Scopus (486) Google Scholar). Both CD2AP and Cin85 contain a motif, FXDXF, that mediates interactions with the α-appendage of clathrin adaptor protein 2 (9Brett T.J. Traub L.M. Fremont D.H. Structure (Camb.). 2002; 10: 797-809Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). Interactions of CD2AP and Cin85 with the phosphatidylinositol bisphosphate-dependent GTPase for ARF1 and ARF5, known as ASAP1, as well as cortactin- and actin-capping protein suggest additional roles in the regulation of the actin cytoskeleton (7Kowanetz K. Husnjak K. Holler D. Kowanetz M. Soubeyran P. Hirsch D. Schmidt M.H. Pavelic K. De Camilli P. Randazzo P.A. Dikic I. Mol. Biol. Cell. 2004; 15: 3155-3166Crossref PubMed Scopus (102) Google Scholar, 10Liu Y. Yerushalmi G.M. Grigera P.R. Parsons J.T. J. Biol. Chem. 2005; 280: 8884-8892Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 11Hutchings N.J. Clarkson N. Chalkley R. Barclay A.N. Brown M.H. J. Biol. Chem. 2003; 278: 22396-22403Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 12Lynch D.K. Winata S.C. Lyons R.J. Hughes W.E. Lehrbach G.M. Wasinger V. Corthals G. Cordwell S. Daly R.J. J. Biol. Chem. 2003; 278: 21805-21813Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). To further elucidate the molecular mechanism of CD2AP function, we performed mass spectrometry to identify interacting proteins. We identified novel and previously known interacting proteins such as actin-capping protein CP (11Hutchings N.J. Clarkson N. Chalkley R. Barclay A.N. Brown M.H. J. Biol. Chem. 2003; 278: 22396-22403Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Over the last decade, there has been much progress in our understanding of how the actin cytoskeleton is regulated. Critical is the polymerization of monomeric G-actin to forming an asymmetric actin filament with a barbed and a pointed end. The barbed end is favored for polymerization. The Arp2/3 complex and formins can nucleate actin polymerization by creating free barbed ends, whereas gelsolin and actin-capping protein CP cap the barbed end (13Cooper J.A. Schafer D.A. Curr. Opin. Cell Biol. 2000; 12: 97-103Crossref PubMed Scopus (264) Google Scholar, 14Harris E.S. Higgs H.N. Curr. Biol. 2004; 14: R520-R522Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). CP is a ubiquitously expressed heterodimer of α and β subunits (15Cooper J.A. Blum J.D. Pollard T.D. J. Cell Biol. 1984; 99: 217-225Crossref PubMed Scopus (68) Google Scholar). It is enriched in lamellipodia, and it plays an important role in cell motility (13Cooper J.A. Schafer D.A. Curr. Opin. Cell Biol. 2000; 12: 97-103Crossref PubMed Scopus (264) Google Scholar). CP binds to the barbed end of the actin filament and prevents the addition and removal of actin subunits (16Wear M.A. Yamashita A. Kim K. Maeda Y. Cooper J.A. Curr. Biol. 2003; 13: 1531-1537Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). By limiting the growth of pre-existing actin filaments, CP enhances new actin filament branching by the Arp2/3 complex (17Pollard T.D. Beltzner C.C. Curr. Opin. Struct. Biol. 2002; 12: 768-774Crossref PubMed Scopus (114) Google Scholar). Recently, several proteins (CARMIL, CKIP-1, and V-1) have been demonstrated to bind and inhibit CP activity (18Canton D.A. Olsten M.E. Kim K. Doherty-Kirby A. Lajoie G. Cooper J.A. Litchfield D.W. Mol. Cell. Biol. 2005; 25: 3519-3534Crossref PubMed Scopus (63) Google Scholar, 19Taoka M. Ichimura T. Wakamiya-Tsuruta A. Kubota Y. Araki T. Obinata T. Isobe T. J. Biol. Chem. 2003; 278: 5864-5870Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 20Yang C. Pring M. Wear M.A. Huang M. Cooper J.A. Svitkina T.M. Zigmond S.H. Dev. Cell. 2005; 9: 209-221Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). To understand the role of CD2AP in actin cytoskeleton dynamics, we decided to focus on characterizing the interaction of CD2AP with CP. Even though this interaction was previously reported (11Hutchings N.J. Clarkson N. Chalkley R. Barclay A.N. Brown M.H. J. Biol. Chem. 2003; 278: 22396-22403Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), the mode of binding and the effect of CD2AP on the activity of CP are not known. In this report, we confirmed the binding of CD2AP with CP, and we mapped the interaction. This allowed us to identify a novel capping protein binding motif recognized by CP that is present in CD2AP, Cin85, CKIP-1, and CARMIL. Co-immunoprecipitation—Co-immunoprecipitations were performed as previously Kim J. M. A. C. H. Shaw A.S. G. T. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). were with for the were with and in 2 and to the was to an for of protein were for at with The were with of for were on and with as previously R.J. K. C. S. Yu J. K. J. G. G. G. M. F. G. I. R. P. A. P. C. T. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar). of was performed as by A. M. O. M. Chem. PubMed Scopus Google Scholar). were the with a and a well of a and of was performed with a as previously T. H. M. K. PubMed Scopus Google Scholar). were the for by mass were by liquid mass spectrometry with a to an mass as previously R.J. K. C. S. Yu J. K. J. G. G. G. M. F. G. I. R. P. A. P. C. T. Mol. Cell. Biol. 2005; 25: PubMed Scopus Google Scholar). were with both the (4Take H. Watanabe S. Takeda K. Yu Z.X. Iwata N. Kajigaya S. Biochem. Biophys. Res. Commun. 2000; 268: 321-328Crossref PubMed Scopus (137) Google Scholar) and proteins were the Biochem. PubMed Scopus Google Scholar). A the CD2AP was cloned with and a of CD2AP the proline-rich was by and cloned the and of The the coiled-coil domain was by of and were by of The was by the as the The was used to with and by in and were by by proteins were expressed in and protein CP and subunits were in the and as previously (16Wear M.A. Yamashita A. Kim K. Maeda Y. Cooper J.A. Curr. Biol. 2003; 13: 1531-1537Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). The CP and were as in M.A. Yamashita A. Kim K. Maeda Y. Cooper J.A. Curr. Biol. 2003; 13: 1531-1537Abstract Full Text Full Text PDF PubMed Scopus (110) Google of all was proteins were by and were the protein and by at were a at and for both binding and was to CD2AP to were the in a and CP was at at a of To the by CP was at and the binding was and The binding were by The was by CD2AP the of the To the binding of of were on the the of the is to the mass of the we for in the molecular of and in the on the the of of This allowed us to a for The binding of the in to the was by the of the CP at to the used for the were by a were by HPLC, and sequences were by mass The sequences of the used CKIP-1, CD2AP, and CD2AP the and were and as in M.A. Yamashita A. Kim K. Maeda Y. Cooper J.A. Curr. Biol. 2003; 13: 1531-1537Abstract Full Text Full Text PDF PubMed Scopus (110) Google was used at a of in polymerization and was for to the of polymerization by a of to to A of polymerization and was to polymerization. CP, and were in and The CP and were to the actin followed by the addition of polymerization followed by of The was and in the with a of The was and at to to for at The binding were was a of the actin polymerization actin and 2 CP. It was performed as in D.A. Cooper J.A. J. Cell Biol. PubMed Scopus Google activity is as the of the of the the addition of CARMIL or of by identify CD2AP-interacting an of CD2AP was in and The proteins were by and The of protein was performed mass In addition to CD2AP, several previously CD2AP-interacting proteins were such as actin S. F. Am. J. 2002; PubMed Scopus Google Scholar), D.K. Winata S.C. Lyons R.J. Hughes W.E. Lehrbach G.M. Wasinger V. Corthals G. Cordwell S. Daly R.J. J. Biol. Chem. 2003; 278: 21805-21813Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), and actin-capping protein CP (11Hutchings N.J. Clarkson N. Chalkley R. Barclay A.N. Brown M.H. J. Biol. Chem. 2003; 278: 22396-22403Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). interacting were also Cin85 (4Take H. Watanabe S. Takeda K. Yu Z.X. Iwata N. Kajigaya S. Biochem. Biophys. Res. Commun. 2000; 268: 321-328Crossref PubMed Scopus (137) Google Scholar, I. Middleton G. Adu J. Ninkina N.N. Drobot L.B. Filonenko V. Matsuka G. Davies A.M. Waterfield M. Buchman V.L. EMBO J. 2000; 19: 4015-4025Crossref PubMed Scopus (121) Google Scholar), S.H. P.A. J.H. L.B. J. Cell Biol. PubMed Scopus Google Scholar), clathrin adaptor protein and proteins K. S. A. K. Hirsch J. Y. Randazzo P.A. Mol. Cell. 2002; 9: Full Text Full Text PDF PubMed Scopus Google Scholar) and P. Y. D. EMBO J. 14: PubMed Scopus Google Scholar), synaptojanin 2 C. D. R. Y. De Camilli P. Nature. PubMed Scopus (486) Google Scholar), protein protein protein and protein A.M. Res. PubMed Scopus Google Scholar). The of proteins involved in actin regulation that CD2AP in the regulation of the actin cytoskeleton. CP plays an important role in the of actin we that CD2AP the activity of CP. We focused on characterizing the interaction of CP with CD2AP in the an interaction of CP with the of with the human of CD2AP, was reported (11Hutchings N.J. Clarkson N. Chalkley R. Barclay A.N. Brown M.H. J. Biol. Chem. 2003; 278: 22396-22403Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). To we a protein of CD2AP and it for interaction with CP surface plasmon CD2AP was on the and CP was used as the the the of CD2AP with CP that this to CP with a of binding of and The of CD2AP is for proline-rich sequences followed by a coiled-coil domain the extreme COOH terminus (1Dustin M.L. Olszowy M.W. Holdorf A.D. Li J. Bromley S. Desai N. Widder P. Rosenberger F. van der Merwe P.A. Allen P.M. Shaw A.S. Cell. 1998; 94: 667-677Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar). We the of the coiled-coil domain for binding to CP by a the coiled-coil domain SPR, we found that this to CP. Therefore, the coiled-coil domain is not for binding we the proline-rich sequences of CD2AP were for A the proline-rich sequences and was and for its to bind CP by This also binding to CP, that the proline-rich sequences were not for binding Therefore, we that the of CD2AP the proline-rich sequences and the coiled-coil domain the CP binding To the interaction we additional this has we the COOH terminus or the end Both binding to CP the binding to The was for because a was to bind to CP by We the binding further by additional both the NH2 and COOH the binding to CP, the and were for CP binding We the binding of this binding of CD2AP with CP. that CD2AP to CP with a of and binding of and this is to the one for the interaction of the of CD2AP with CP, this was to for CP CP is a heterodimer of α and β The COOH of both subunits are known to important for its actin-capping activity (16Wear M.A. Yamashita A. Kim K. Maeda Y. Cooper J.A. Curr. Biol. 2003; 13: 1531-1537Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). To the of for the interaction with CD2AP, CP the α the β or both were for binding to CP the α or both the α and β COOH not interact with CD2AP, whereas CP the β an binding CD2AP both α and β COOH of CP for results that CD2AP inhibit capping activity of CP. of CP the binding for and were reported (18Canton D.A. Olsten M.E. Kim K. Doherty-Kirby A. Lajoie G. Cooper J.A. Litchfield D.W. Mol. Cell. Biol. 2005; 25: 3519-3534Crossref PubMed Scopus (63) Google Scholar, 20Yang C. Pring M. Wear M.A. Huang M. Cooper J.A. Svitkina T.M. Zigmond S.H. Dev. Cell. 2005; 9: 209-221Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). To binding to of CD2AP, we performed a The in that all three proteins a of LXHXTXXRPK(X)6P is that this the CP binding To the in this motif are important for CP we of the to in the was for CP binding of the and whereas of the other not of in CD2AP, and not binding of CP to Therefore, we that the LXHXTXXRPK(X)6P motif in CD2AP is for To that the LXHXTXXRPK(X)6P motif found in all three proteins and is the binding we to this motif and CARMIL in a the CD2AP The of the and CARMIL to inhibit CD2AP binding to CP confirmed that all three of proteins this motif to bind to CP, and this motif is for of CP by both the activity and CD2AP binding the of CP, we were to CD2AP binding This was a polymerization for barbed end growth in as The polymerization of as by its was The addition of to to the not have effect on actin and as the addition of CP barbed end of to CP the activity of CP in a A effect was with the addition of the binding domain not The effect of CD2AP on the activity of CP was the this is much the of CP for CD2AP, we suggest that the of CP by CD2AP is not The effect of CD2AP on CP actin-capping activity was confirmed a polymerization In this the effect of CD2AP was allowed to to by the to to actin was the of CD2AP for CP was found to to that by In because the activity of CP was not this that the complex shown in the complex actin polymerization not been that the complex a for the barbed end. the results that CD2AP inhibits the capping activity of CP and that the complex has the to cap the barbed end at a much The of CD2AP to actin was also was to actin polymerization CP at a of the barbed were The addition of in actin with the of CP In this report, we present the role of CD2AP as a of the actin cytoskeleton. In a we identified several actin proteins with CD2AP, actin capping and By its interaction with CP, we identified a novel motif in CD2AP that is also found in Cin85, CKIP-1, and CARMIL that mediates binding to CP. CD2AP inhibits the activity of CP, the interaction CP and CD2AP to In the we identified known CD2AP-interacting capping protein and (11Hutchings N.J. Clarkson N. Chalkley R. Barclay A.N. Brown M.H. J. Biol. Chem. 2003; 278: 22396-22403Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 12Lynch D.K. Winata S.C. Lyons R.J. Hughes W.E. Lehrbach G.M. Wasinger V. Corthals G. Cordwell S. Daly R.J. J. Biol. Chem. 2003; 278: 21805-21813Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). is reported to bind to Cin85 has not been reported to bind to CD2AP (7Kowanetz K. Husnjak K. Holler D. Kowanetz M. Soubeyran P. Hirsch D. Schmidt M.H. Pavelic K. De Camilli P. Randazzo P.A. Dikic I. Mol. Biol. Cell. 2004; 15: 3155-3166Crossref PubMed Scopus (102) Google Scholar). We also identified new proteins. the clathrin adaptor protein 2 was implicated as a CD2AP-interacting protein because of the of the binding motif (9Brett T.J. Traub L.M. Fremont D.H. Structure (Camb.). 2002; 10: 797-809Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar), this is the that CD2AP in bind to novel interactions and are proteins for the and K. S. A. K. Hirsch J. Y. Randazzo P.A. Mol. Cell. 2002; 9: Full Text Full Text PDF PubMed Scopus Google Scholar, P. Y. D. EMBO J. 14: PubMed Scopus Google Scholar). We also identified a protein with actin binding is a known inhibitor of actin polymerization S.H. P.A. J.H. L.B. J. Cell Biol. PubMed Scopus Google Scholar). the other we not other reported such as or the of phosphatidylinositol 3-kinase S. H. S. A. 1999; PubMed Scopus Google Scholar). This because proteins have a or interaction with It is also that the we used in our not binding to We also identified other proteins of such as protein and the and protein A.M. Res. PubMed Scopus Google Scholar). to the of To the we mapped the binding of CD2AP to This domain not have and is the proline-rich sequences and coiled-coil domain at the COOH terminus. a to this to the sequences of other known and we identified the novel motif This motif is also found in Cin85. the of the of this T. K. J.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that a to the motif we is present in all known of CARMIL. of all of the that are important for with and the critical with our of the in CARMIL was shown to important for CP binding C. Pring M. Wear M.A. Huang M. Cooper J.A. Svitkina T.M. Zigmond S.H. Dev. Cell. 2005; 9: 209-221Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). of CD2AP is in Cin85 and however, it is in CKIP-1. In the to CP that an at this To address we a with for in CD2AP and its to bind to CP. this binding with CD2AP not This confirmed that the in CD2AP is important for binding and that the binding and CD2AP is not to the The of CKIP-1, however, suggest that there is a of of the binding that the binding motif that we identified It is to that the and are play important roles in We the for other proteins this motif not identify it is that proteins are the only molecules this motif, it that of this motif our that this motif is used by CD2AP, CKIP-1, and CARMIL to bind to CP. The COOH of both the α and β subunits of CP are important for its capping activity (16Wear M.A. Yamashita A. Kim K. Maeda Y. Cooper J.A. Curr. Biol. 2003; 13: 1531-1537Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), and were also important for CD2AP The interaction of CARMIL with CP, however, not the α or β COOH of CP for binding C. Pring M. Wear M.A. Huang M. Cooper J.A. Svitkina T.M. Zigmond S.H. Dev. Cell. 2005; 9: 209-221Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). the of CARMIL used was much the of CD2AP this that CARMIL interact with other of CP in addition to the that was with CARMIL to additional interacting the β was involved in CD2AP and the and in this Cooper J.A. J. Cell Biol. 1999; PubMed Scopus Google Scholar), we the CD2AP interaction with CP was β The of CP binding to CD2AP not This that CD2AP interacts with the of the and or that the of the β COOH terminus is not suggest that CD2AP can actin by CP by of the barbed end. to we found that CD2AP not the capping activity of CP C. Pring M. Wear M.A. Huang M. Cooper J.A. Svitkina T.M. Zigmond S.H. Dev. Cell. 2005; 9: 209-221Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). of CD2AP, capping activity of CP was this to the that we only of CD2AP the we are by the that CD2AP binding to CP function to and not inhibit its the of CP and CD2AP in in the is the of CP for the barbed ends, the complex is to capping activity in the of identified the for to the binding of CP in for a of actin filament This not the only CD2AP the actin cytoskeleton. to we found that CD2AP can barbed end (18Canton D.A. Olsten M.E. Kim K. Doherty-Kirby A. Lajoie G. Cooper J.A. Litchfield D.W. Mol. Cell. Biol. 2005; 25: 3519-3534Crossref PubMed Scopus (63) Google Scholar, 20Yang C. Pring M. Wear M.A. Huang M. Cooper J.A. Svitkina T.M. Zigmond S.H. Dev. Cell. 2005; 9: 209-221Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). CD2AP CARMIL as the only known proteins to barbed the high of CD2AP for CP, it that much of the CP to CD2AP in the the of identified it that of CP to proteins. CD2AP and its homolog Cin85 can form by coiled-coil domain and A. S. and both can bind to CP, it is that form a complex in It to how are in because CD2AP is with other actin proteins such as D.K. Winata S.C. Lyons R.J. Hughes W.E. Lehrbach G.M. Wasinger V. Corthals G. Cordwell S. Daly R.J. J. Biol. Chem. 2003; 278: 21805-21813Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). The role of CD2AP in actin regulation We are to roles CD2AP plays in other of actin polymerization. Recently, S. D.A. Svitkina T.M. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) have demonstrated that the and is on CP. CP is actin are favored actin it is that of CD2AP to the inhibit CP activity and function to or the of we were to this in of CD2AP-deficient with not motility not In of a of CD2AP the capping binding to the not of CD2AP also effect on the actin cytoskeleton. the of Cin85 a in our results suggest that in the actin cytoskeleton for the for renal We however, to the actin and molecule is by We for the and for

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