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• W2077117003 abstract "Transglutaminase 2 (TG2) is a multifunctional protein that has been implicated in numerous pathologies including that of neurodegeneration and celiac disease, but the molecular interactions that mediate its diverse activities are largely unknown. Bcr and the closely related Abr negatively regulate the small G-protein Rac: loss of their combined function in vivo results in increased reactivity of innate immune cells. Bcr and Abr are GTPase-activating proteins that catalyze the hydrolysis of the GTP bound to Rac. However, how the Bcr and Abr GTPase-activating activity is regulated is not precisely understood. We here report a novel mechanism of regulation through direct protein-protein interaction with TG2. TG2 bound to the Rac-binding pocket in the GTPase-activating domains of Bcr and Abr, blocked Bcr activity and, through this mechanism, increased levels of active GTP-bound Rac and EGF-stimulated membrane ruffling. TG2 exists in at least two different conformations. Interestingly, experiments using TG2 mutants showed that Bcr exhibits preferential binding to the non-compacted conformation of TG2, in which its catalytic domain is exposed, but transamidation is not needed for the interaction. Thus, TG2 regulates levels of cellular GTP-bound Rac and actin cytoskeletal reorganization through a new mechanism involving direct inhibition of Bcr GTPase-activating activity. Transglutaminase 2 (TG2) is a multifunctional protein that has been implicated in numerous pathologies including that of neurodegeneration and celiac disease, but the molecular interactions that mediate its diverse activities are largely unknown. Bcr and the closely related Abr negatively regulate the small G-protein Rac: loss of their combined function in vivo results in increased reactivity of innate immune cells. Bcr and Abr are GTPase-activating proteins that catalyze the hydrolysis of the GTP bound to Rac. However, how the Bcr and Abr GTPase-activating activity is regulated is not precisely understood. We here report a novel mechanism of regulation through direct protein-protein interaction with TG2. TG2 bound to the Rac-binding pocket in the GTPase-activating domains of Bcr and Abr, blocked Bcr activity and, through this mechanism, increased levels of active GTP-bound Rac and EGF-stimulated membrane ruffling. TG2 exists in at least two different conformations. Interestingly, experiments using TG2 mutants showed that Bcr exhibits preferential binding to the non-compacted conformation of TG2, in which its catalytic domain is exposed, but transamidation is not needed for the interaction. Thus, TG2 regulates levels of cellular GTP-bound Rac and actin cytoskeletal reorganization through a new mechanism involving direct inhibition of Bcr GTPase-activating activity. IntroductionTransglutaminase 2 (TG2, 2The abbreviations used are: TG2transglutaminase 2EGFepidermal growth factorGAPGTPase-activating proteinGDIguanine nucleotide dissociation inhibitorGEFguanine nucleotide exchange factorHBMEChuman brain microvascular endothelial cellsIPimmunoprecipitationPBSphosphate-buffered salinePDpull-downGTPγSguanosine 5′-3-O-(thio)triphosphateWTwild type. also called tissue transglutaminase) is a member of the transglutaminase family that selectively catalyzes the Ca2+-dependent formation of covalent bonds between δ-carboxamide groups of glutamine residues and ϵ-amino groups of lysine residues or primary amines. Unlike other family members, TG2 is expressed in many tissues and cell types, also functions as a G protein in transmembrane signaling, and acts as a cell surface adhesion mediator (1.Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar, 2.Griffin M. Casadio R. Bergamini C.M. Biochem. J. 2002; 368: 377-396Crossref PubMed Scopus (851) Google Scholar, 3.Janiak A. Zemskov E.A. Belkin A.M. Mol. Biol. Cell. 2006; 17: 1606-1619Crossref PubMed Scopus (95) Google Scholar, 4.Zemskov E.A. Janiak A. Hang J. Waghray A. Belkin A.M. Front Biosci. 2006; 11: 1057-1076Crossref PubMed Scopus (146) Google Scholar). TG2 has been the focus of numerous studies that show it plays an important role in a variety of biological functions including differentiation, apoptosis, signaling, adhesion, migration, wound healing, inflammation, and phagocytosis of apoptotic cells. Although TG2 appears to have many functional domains, studies have mainly concentrated on its cross-linking activity, with little investigation into its non-enzymatic roles (3.Janiak A. Zemskov E.A. Belkin A.M. Mol. Biol. Cell. 2006; 17: 1606-1619Crossref PubMed Scopus (95) Google Scholar).Bcr was originally identified through its involvement in chronic myeloid leukemia (5.Heisterkamp N. Groffen J. Chronic Myeloid Leukemia: Biology and Treatment.in: Carella A.M. Daley G.Q. Eaves C.J. Goldman J.M. Hehlman R. Martin Dunitz, Ltd., London2001: 3-17Google Scholar). Subsequent studies established that it contains a domain with GTPase-activating protein (GAP) activity for the Rho family of small GTPases that includes Rho, Rac and Cdc42 (6.Diekmann D. Brill S. Garrett M.D. Totty N. Hsuan J. Monfries C. Hall C. Lim L. Hall A. Nature. 1991; 351: 400-402Crossref PubMed Scopus (354) Google Scholar). Although the purified GAP domain of Bcr and of the highly related Abr are active toward both Rac and Cdc42 in vitro (7.Chuang T.H. Xu X. Kaartinen V. Heisterkamp N. Groffen J. Bokoch G.M. Proc. Natl. Acad. Sci. U.S.A. 1995; 92: 10282-10286Crossref PubMed Scopus (151) Google Scholar), they only act on Rac in vivo (8.Cho Y.J. Cunnick J.M. Yi S.J. Kaartinen V. Groffen J. Heisterkamp N. Mol. Cell. Biol. 2007; 27: 899-911Crossref PubMed Scopus (53) Google Scholar, 9.Cunnick J.M. Schmidhuber S. Chen G. Yu M. Yi S.J. Cho Y.J. Kaartinen V. Minoo P. Warburton D. Groffen J. Heisterkamp N. Mol. Cell. Biol. 2009; 29: 5742-5750Crossref PubMed Scopus (26) Google Scholar, 10.Kaartinen V. Gonzalez-Gomez I. Voncken J.W. Haataja L. Faure E. Nagy A. Groffen J. Heisterkamp N. Development. 2001; 128: 4217-4227Crossref PubMed Google Scholar).Rho family members are critical regulators of a variety of cellular functions including actin cytoskeleton rearrangement, growth, differentiation, and membrane trafficking (11.Bishop A.L. Hall A. Biochem. J. 2000; 348: 241-255Crossref PubMed Scopus (1660) Google Scholar, 12.Bokoch G.M. Trends Cell Biol. 2005; 15: 163-171Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 13.Vega F.M. Ridley A.J. FEBS Lett. 2008; 582: 2093-2101Crossref PubMed Scopus (599) Google Scholar, 14.Heasman S.J. Ridley A.J. Nat. Rev. Mol. Cell Biol. 2008; 9: 690-701Crossref PubMed Scopus (1406) Google Scholar). They act as molecular switches that cycle between an active, GTP-bound and an inactive, GDP-bound form. This cycle is tightly controlled by GAPs such as Bcr and Abr, by guanine nucleotide exchange factors (GEFs), and by guanine nucleotide dissociation inhibitors (GDIs). Although many studies have focused on activation of Rho GTPases, the deactivation by GAPs plays an equally important critical role in their regulation (15.Moon S.Y. Zheng Y. Trends Cell Biol. 2003; 13: 13-22Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar, 16.Bernards A. Settleman J. Trends Cell Biol. 2004; 14: 377-385Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 17.Bernards A. Settleman J. Growth Factors. 2005; 23: 143-149Crossref PubMed Scopus (65) Google Scholar). For example, loss of the tumor suppressor DLC1, a RhoGAP, is associated with the development of hepatocellular carcinoma in man (18.Lahoz A. Hall A. Genes Dev. 2008; 22: 1724-1730Crossref PubMed Scopus (76) Google Scholar).How the GAP activity of such proteins is regulated is not completely understood. The Bcr protein contains multiple domains that could be involved in regulation of the GAP activity. We recently identified a direct interaction with RhoGDI as one regulatory mechanism (19.Kweon S.M. Cho Y.J. Minoo P. Groffen J. Heisterkamp N. J. Biol. Chem. 2008; 283: 3023-3030Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). However, it is likely that Bcr is regulated though multiple, different interactions. In an alternative approach to investigate how Bcr is regulated, we sought to identify Bcr-interacting proteins in a yeast two-hybrid screen, using the entire Bcr protein as bait, and isolated TG2. We here report that TG2 functions as a regulator of the BcrGAP activity, and, through it, controls levels of activated Rac. Furthermore, GTP-bound TG2 has reduced affinity for Bcr and reduced ability to inhibit the Bcr GAP activity.DISCUSSIONTG2 is a large multidomain protein with interesting but very complex activity and regulation in vivo and in vitro. A number of studies are consistent with a model in which TG2 exists in at least two distinct conformations, which may be dependent upon the physiological state of a cell. The so-called closed conformation is adopted when TG2 is guanine nucleotide-bound. In this form of TG2, the catalytic core domain is hidden, access to the domain is blocked, and the protein is inactive as transamidase. In contrast, the conformation of guanine nucleotide-free or Ca2+-activated TG2 is open (2.Griffin M. Casadio R. Bergamini C.M. Biochem. J. 2002; 368: 377-396Crossref PubMed Scopus (851) Google Scholar, 28.Pinkas D.M. Strop P. Brunger A.T. Khosla C. PLoS Biol. 2007; 5: e327Crossref PubMed Scopus (327) Google Scholar, 29.Liu S. Cerione R.A. Clardy J. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 2743-2747Crossref PubMed Scopus (276) Google Scholar). TG2 mutants such as R580A and S171E are unable to bind guanine nucleotides and are locked in this non-compacted conformation, exposing the catalytic core domain (22.Datta S. Antonyak M.A. Cerione R.A. Biochemistry. 2006; 45: 13163-13174Crossref PubMed Scopus (34) Google Scholar, 30.Begg G.E. Carrington L. Stokes P.H. Matthews J.M. Wouters M.A. Husain A. Lorand L. Iismaa S.E. Graham R.M. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 19683-19688Crossref PubMed Scopus (108) Google Scholar). Our studies are consistent with a model in which the interaction between Bcr and TG2 is conformation dependent, taking place preferentially with the more open conformation of TG2 (Fig. 5). First, Bcr binds to the catalytic core domain of TG2, which is exposed in the open conformation. Second, the R580A and S171E mutants showed a very strong interaction with Bcr. Third, we found that the binding of TG2 to BcrGAP was increased in the presence of Ca2+ (data not shown). However, although Bcr bound to the TG2 catalytic core, the interaction was independent of the catalytic core domain being active as transamidase.The interaction between Bcr and TG2 was measured under normal physiological conditions, indicating that the more open conformation of TG2 is present in non-stressed cells. Many signal transduction pathways including those of EGF lead to transient increases in intracellular free Ca2+ that could locally induce the open conformation of TG2 (31.Noh D.Y. Shin S.H. Rhee S.G. Biochim. Biophys. Acta. 1995; 1242: 99-113Crossref PubMed Scopus (254) Google Scholar). Indeed, Antonyak et al. (21.Antonyak M.A. Li B. Regan A.D. Feng Q. Dusaban S.S. Cerione R.A. J. Biol. Chem. 2009; 284: 17914-17925Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) showed that HeLa cells stimulated with EGF contain both GTP-bound TG2 and transamidase-proficient TG2.Interestingly, stimulation of the α1B-adrenergic receptor with epinephrine results in the activation of PLCδ1, the exchange of GDP for GTP on TG2 mediated by PLCδ1, and the release of calcium from intracellular stores (32.Baek K.J. Kang S.K. Damron D. Im M. J. Biol. Chem. 2001; 276: 5591-5597Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Thus, it is possible that TG2 undergoes a number of rapid conformational switches upon cell signaling, with an initially GTP-bound, effector binding state followed by a calcium-bound state that exposes the CD domain for interaction with proteins such as Bcr.Our studies show that TG2 plays a role in the normal regulation of Bcr activity and through it, of Rac activation, and cytoskeletal organization. Although there have been a number of previous reports showing that TG2 can regulate Rho and Rho family-controlled processes, these studies either reported a different molecular mechanism or did not clearly identify one. One mechanism described involves the post-translational modification/transamidation activity of TG2, which may be relatively irreversible: when TG2 is activated by retinoic acid, it can directly modify and activate RhoA by transamidation, resulting in Rho-associated kinase-2 activation (33.Singh U.S. Kunar M.T. Kao Y.L. Baker K.M. EMBO J. 2001; 20: 2413-2423Crossref PubMed Scopus (80) Google Scholar). TG2 can additionally activate Rac1 and RhoA by their transamidation to serotonin (34.Dai Y. Dudek N.L. Patel T.B. Muma N.A. J. Pharmacol. Exp. Ther. 2008; 326: 153-162Crossref PubMed Scopus (40) Google Scholar, 35.Guilluy C. Rolli-Derkinderen M. Tharaux P.L. Melino G. Pacaud P. Loirand G. J. Biol. Chem. 2007; 282: 2918-2928Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar). Cell surface TG2 was reported to regulate RhoA activity via a non-enzymatic mechanism involving integrin clustering (3.Janiak A. Zemskov E.A. Belkin A.M. Mol. Biol. Cell. 2006; 17: 1606-1619Crossref PubMed Scopus (95) Google Scholar). Also, Toth et al. (36.Tóth B. Garabuczi E. Sarang Z. Vereb G. Vámosi G. Aeschlimann D. Blaskó B. Bécsi B. Erdõdi F. Lacy-Hulbert A. Zhang A. Falasca L. Birge R.B. Balajthy Z. Melino G. Fésüs L. Szondy Z. J. Immunol. 2009; 182: 2084-2092Crossref PubMed Scopus (118) Google Scholar) proposed that TG2 plays a role in Rac activation via integrin β3.In addition, there have been several other studies showing that TG2 is involved in processes needing actin cytoskeletal reorganization (26.Yi S.J. Choi H.J. Yoo J.O. Yuk J.S. Jung H.I. Lee S.H. Han J.A. Kim Y.M. Ha K.S. Biochem. Biophys. Res. Commun. 2004; 325: 819-826Crossref PubMed Scopus (25) Google Scholar, 36.Tóth B. Garabuczi E. Sarang Z. Vereb G. Vámosi G. Aeschlimann D. Blaskó B. Bécsi B. Erdõdi F. Lacy-Hulbert A. Zhang A. Falasca L. Birge R.B. Balajthy Z. Melino G. Fésüs L. Szondy Z. J. Immunol. 2009; 182: 2084-2092Crossref PubMed Scopus (118) Google Scholar), a Rho family member-regulated process. Antonyak et al. (21.Antonyak M.A. Li B. Regan A.D. Feng Q. Dusaban S.S. Cerione R.A. J. Biol. Chem. 2009; 284: 17914-17925Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) recently reported that TG2 is an essential component of EGF-stimulated migration. Interestingly, they showed that the TG2 R580L and C277V mutants, which bind to Bcr, both localize to the leading edge of cells. They speculate that the active site of TG2 may be involved in the direct binding to actin and act as a scaffold for the recruitment of other proteins that influence actin polymerization. This would be consistent with the results of our own studies, which show that TG2 binds to the Rac regulatory protein Bcr.Thus, TG2 clearly is involved in the regulation of Rac, and it will be of interest to determine if the regulation is associated only with maintenance of normal cell homeostasis, or if it can be linked to apoptosis/cell death and/or pathologies such as celiac and neurodegenerative diseases. Our other studies 3N. Heisterkamp, manuscript in preparation. show that TG2 can also use Bcr as a substrate and cross-link it. The combined data will allow us to start to dissect how TG2 regulates Rac under normal and pathological conditions. IntroductionTransglutaminase 2 (TG2, 2The abbreviations used are: TG2transglutaminase 2EGFepidermal growth factorGAPGTPase-activating proteinGDIguanine nucleotide dissociation inhibitorGEFguanine nucleotide exchange factorHBMEChuman brain microvascular endothelial cellsIPimmunoprecipitationPBSphosphate-buffered salinePDpull-downGTPγSguanosine 5′-3-O-(thio)triphosphateWTwild type. also called tissue transglutaminase) is a member of the transglutaminase family that selectively catalyzes the Ca2+-dependent formation of covalent bonds between δ-carboxamide groups of glutamine residues and ϵ-amino groups of lysine residues or primary amines. Unlike other family members, TG2 is expressed in many tissues and cell types, also functions as a G protein in transmembrane signaling, and acts as a cell surface adhesion mediator (1.Fesus L. Piacentini M. Trends Biochem. Sci. 2002; 27: 534-539Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar, 2.Griffin M. Casadio R. Bergamini C.M. Biochem. J. 2002; 368: 377-396Crossref PubMed Scopus (851) Google Scholar, 3.Janiak A. Zemskov E.A. Belkin A.M. Mol. Biol. Cell. 2006; 17: 1606-1619Crossref PubMed Scopus (95) Google Scholar, 4.Zemskov E.A. Janiak A. Hang J. Waghray A. Belkin A.M. Front Biosci. 2006; 11: 1057-1076Crossref PubMed Scopus (146) Google Scholar). TG2 has been the focus of numerous studies that show it plays an important role in a variety of biological functions including differentiation, apoptosis, signaling, adhesion, migration, wound healing, inflammation, and phagocytosis of apoptotic cells. Although TG2 appears to have many functional domains, studies have mainly concentrated on its cross-linking activity, with little investigation into its non-enzymatic roles (3.Janiak A. Zemskov E.A. Belkin A.M. Mol. Biol. Cell. 2006; 17: 1606-1619Crossref PubMed Scopus (95) Google Scholar).Bcr was originally identified through its involvement in chronic myeloid leukemia (5.Heisterkamp N. Groffen J. Chronic Myeloid Leukemia: Biology and Treatment.in: Carella A.M. Daley G.Q. Eaves C.J. Goldman J.M. Hehlman R. Martin Dunitz, Ltd., London2001: 3-17Google Scholar). Subsequent studies established that it contains a domain with GTPase-activating protein (GAP) activity for the Rho family of small GTPases that includes Rho, Rac and Cdc42 (6.Diekmann D. Brill S. Garrett M.D. Totty N. Hsuan J. Monfries C. Hall C. Lim L. Hall A. Nature. 1991; 351: 400-402Crossref PubMed Scopus (354) Google Scholar). Although the purified GAP domain of Bcr and of the highly related Abr are active toward both Rac and Cdc42 in vitro (7.Chuang T.H. Xu X. Kaartinen V. Heisterkamp N. Groffen J. Bokoch G.M. Proc. Natl. Acad. Sci. U.S.A. 1995; 92: 10282-10286Crossref PubMed Scopus (151) Google Scholar), they only act on Rac in vivo (8.Cho Y.J. Cunnick J.M. Yi S.J. Kaartinen V. Groffen J. Heisterkamp N. Mol. Cell. Biol. 2007; 27: 899-911Crossref PubMed Scopus (53) Google Scholar, 9.Cunnick J.M. Schmidhuber S. Chen G. Yu M. Yi S.J. Cho Y.J. Kaartinen V. Minoo P. Warburton D. Groffen J. Heisterkamp N. Mol. Cell. Biol. 2009; 29: 5742-5750Crossref PubMed Scopus (26) Google Scholar, 10.Kaartinen V. Gonzalez-Gomez I. Voncken J.W. Haataja L. Faure E. Nagy A. Groffen J. Heisterkamp N. Development. 2001; 128: 4217-4227Crossref PubMed Google Scholar).Rho family members are critical regulators of a variety of cellular functions including actin cytoskeleton rearrangement, growth, differentiation, and membrane trafficking (11.Bishop A.L. Hall A. Biochem. J. 2000; 348: 241-255Crossref PubMed Scopus (1660) Google Scholar, 12.Bokoch G.M. Trends Cell Biol. 2005; 15: 163-171Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 13.Vega F.M. Ridley A.J. FEBS Lett. 2008; 582: 2093-2101Crossref PubMed Scopus (599) Google Scholar, 14.Heasman S.J. Ridley A.J. Nat. Rev. Mol. Cell Biol. 2008; 9: 690-701Crossref PubMed Scopus (1406) Google Scholar). They act as molecular switches that cycle between an active, GTP-bound and an inactive, GDP-bound form. This cycle is tightly controlled by GAPs such as Bcr and Abr, by guanine nucleotide exchange factors (GEFs), and by guanine nucleotide dissociation inhibitors (GDIs). Although many studies have focused on activation of Rho GTPases, the deactivation by GAPs plays an equally important critical role in their regulation (15.Moon S.Y. Zheng Y. Trends Cell Biol. 2003; 13: 13-22Abstract Full Text Full Text PDF PubMed Scopus (482) Google Scholar, 16.Bernards A. Settleman J. Trends Cell Biol. 2004; 14: 377-385Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 17.Bernards A. Settleman J. Growth Factors. 2005; 23: 143-149Crossref PubMed Scopus (65) Google Scholar). For example, loss of the tumor suppressor DLC1, a RhoGAP, is associated with the development of hepatocellular carcinoma in man (18.Lahoz A. Hall A. Genes Dev. 2008; 22: 1724-1730Crossref PubMed Scopus (76) Google Scholar).How the GAP activity of such proteins is regulated is not completely understood. The Bcr protein contains multiple domains that could be involved in regulation of the GAP activity. We recently identified a direct interaction with RhoGDI as one regulatory mechanism (19.Kweon S.M. Cho Y.J. Minoo P. Groffen J. Heisterkamp N. J. Biol. Chem. 2008; 283: 3023-3030Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). However, it is likely that Bcr is regulated though multiple, different interactions. In an alternative approach to investigate how Bcr is regulated, we sought to identify Bcr-interacting proteins in a yeast two-hybrid screen, using the entire Bcr protein as bait, and isolated TG2. We here report that TG2 functions as a regulator of the BcrGAP activity, and, through it, controls levels of activated Rac. Furthermore, GTP-bound TG2 has reduced affinity for Bcr and reduced ability to inhibit the Bcr GAP activity." @default.
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• W2077117003 title "Transglutaminase 2 Regulates the GTPase-activating Activity of Bcr" @default.
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