Class- and Splice Variant-specific Association of CD98 with Integrin β Cytoplasmic Domains

CD98 is a type II transmembrane protein involved in neutral and basic amino acid transport and in cell fusion events. CD98 was implicated in the function of integrin adhesion receptors by its capacity to reverse suppression of integrin activation by isolated integrin β1A domains. Here we report that CD98 associates with integrin β cytoplasmic domains with a unique integrin class and splice variant specificity. In particular, CD98 interacted with the ubiquitous β1A but not the muscle-specific splice variant, β1D, or leukocyte-specific β7 cytoplasmic domains. The ability of CD98 to associate with integrin cytoplasmic domains correlated with its capacity to reverse suppression of integrin activation. The association of CD98 with integrin β1A cytoplasmic domains may regulate the function and localization of these membrane proteins. CD98 is a type II transmembrane protein involved in neutral and basic amino acid transport and in cell fusion events. CD98 was implicated in the function of integrin adhesion receptors by its capacity to reverse suppression of integrin activation by isolated integrin β1A domains. Here we report that CD98 associates with integrin β cytoplasmic domains with a unique integrin class and splice variant specificity. In particular, CD98 interacted with the ubiquitous β1A but not the muscle-specific splice variant, β1D, or leukocyte-specific β7 cytoplasmic domains. The ability of CD98 to associate with integrin cytoplasmic domains correlated with its capacity to reverse suppression of integrin activation. The association of CD98 with integrin β1A cytoplasmic domains may regulate the function and localization of these membrane proteins. complementation of dominant suppression polyacrylamide gel electrophoresis 1,4-piperazinediethanesulfonic acid The development and function of multicellular animals requires integrin adhesion receptors (1.Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (9026) Google Scholar). Integrin-dependent cell adhesion is regulated, in part, by ligand binding affinity (“activation”) changes controlled by cellular signaling cascades (1.Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (9026) Google Scholar, 2.Schwartz M.A. Schaller M.D. Ginsberg M.H. Annu. Rev. Cell Dev. Biol. 1995; 11: 549-599Crossref PubMed Scopus (1474) Google Scholar, 3.Hughes P.E. Renshaw M.W. Pfaff M. Forsyth J. Keivens V.M. Schwartz M.A. Ginsberg M.H. Cell. 1997; 88: 521-530Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). Regulation of integrin affinity is important in cell migration (4.Huttenlocher A. Ginsberg M.H. Horwitz A.F. J. Cell Biol. 1996; 134: 1551-1562Crossref PubMed Scopus (314) Google Scholar, 5.Huttenlocher A. Palecek S.P. Lu Q. Zhang W. Mellgren R.L. Lauffenburger D.A. Ginsberg M.H. Horwitz A.F. J. Biol. Chem. 1997; 272: 32719-32722Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 6.Filardo E.J. Brooks P.C. Deming S.L. Damsky C. Cheresh D.A. J. Cell Biol. 1995; 130: 441-450Crossref PubMed Scopus (182) Google Scholar), extracellular matrix assembly (7.Wu C. Keivens V.M. O'Toole T.E. McDonald J.A. Ginsberg M.H. Cell. 1995; 83: 715-724Abstract Full Text PDF PubMed Scopus (301) Google Scholar), and morphogenesis (8.Martin-Bermudo M.D. Dunin-Borkowski O.M. Brown N.H. J. Cell Biol. 1998; 141: 1073-1081Crossref PubMed Scopus (51) Google Scholar). Integrin activation is energy-dependent and is mediated by cell type specific signals operating through integrin cytoplasmic domains (9.O'Toole T.E. Katagiri Y. Faull R.J. Peter K. Tamura R.N. Quaranta V. Loftus J.C. Shattil S.J. Ginsberg M.H. J. Cell Biol. 1994; 124: 1047-1059Crossref PubMed Scopus (581) Google Scholar). Complementation of dominant suppression (CODS)1 is an expression cloning scheme used to identify proteins that modulate integrin affinity (10.Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 370: 81-85Crossref Scopus (260) Google Scholar). CODS depends on the ability of an isolated integrin β1A cytoplasmic domain, in the form of a chimera with the α subunit of the interleukin-2 receptor, to block integrin activation (dominant suppression). Proteins involved in integrin activation are isolated by their ability to complement dominant suppression. CD98, a type II transmembrane protein first discovered as a T-cell activation antigen (11.Haynes B.F. Hemler M.E. Mann D.L. Eisenbarth G.S. Shelhamer J. Mostowski H.S. Thomas C.A. Strominger J.L. Fauci A.S. J. Immunol. 1981; 126: 1409-1414PubMed Google Scholar), was identified utilizing CODS. CD98, although widely expressed on proliferating cells, is generally down-regulated in quiescent cells (12.Diaz Jr., L.A. Fox D.A. J. Biol. Reg. Homeostat. Agents. 1998; 12: 25-32PubMed Google Scholar). CD98 forms disulfide-bonded heterodimers with several light chains that strongly resemble permeases (13.Mannion B.A. Kolesnikova T.V. Lin S.W. Wang S. Thompson N.L. Hemler M.E. J. Biol. Chem. 1998; 273: 33127-33129Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 14.Kanai Y. Segawa H. Miyamoto K. Uchino H. Takeda E. Endou H. J. Biol. Chem. 1998; 273: 23629-23632Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar, 15.Torrents D. Estevez R. Pineda M. Fernandez E. Lloberas J. Shi Y.-B. Zorzano A. Palacin M. J. Biol. Chem. 1998; 273: 32437-32445Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 16.Estevez R. Camps M. Rojas A.M. Tesrar X. Deves R. Hediger M.A. Zorzano A. Palacin M. FASEB. 1998; 12: 1319-1329Crossref PubMed Scopus (72) Google Scholar, 17.Mastroberardino L. Spindler B. Pfeiffer R. Loffing J. Skelley P.J. Shoemaker C.B. Verrey F. Nature. 1998; 395: 288-291Crossref PubMed Scopus (470) Google Scholar, 18.Pfeiffer R. Rossier G. Spindler B. Meier C. Kuhn L. Verrey F. EMBO J. 1999; 18: 49-57Crossref PubMed Scopus (239) Google Scholar, 19.Pfeiffer R. Spindler B. Loffing J. Skelley P.J. Shoemaker C.B. Verrey F. FEBS Lett. 1998; 439: 157-162Crossref PubMed Scopus (90) Google Scholar, 20.Tsurudome M. Ito M. Takebayashi S. Okumura K. Nishio M. Kawano M. Kusawaga S. Komada S. Ito Y. J. Immunol. 1999; 162: 2462-2466PubMed Google Scholar). CD98 regulates the transport of neutral and positively charge amino acids through these light chains (14.Kanai Y. Segawa H. Miyamoto K. Uchino H. Takeda E. Endou H. J. Biol. Chem. 1998; 273: 23629-23632Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar, 15.Torrents D. Estevez R. Pineda M. Fernandez E. Lloberas J. Shi Y.-B. Zorzano A. Palacin M. J. Biol. Chem. 1998; 273: 32437-32445Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 17.Mastroberardino L. Spindler B. Pfeiffer R. Loffing J. Skelley P.J. Shoemaker C.B. Verrey F. Nature. 1998; 395: 288-291Crossref PubMed Scopus (470) Google Scholar, 18.Pfeiffer R. Rossier G. Spindler B. Meier C. Kuhn L. Verrey F. EMBO J. 1999; 18: 49-57Crossref PubMed Scopus (239) Google Scholar). Thus, CODS has identified an unexpected connection between cell adhesion and certain amino acid transporters. The mechanism by which CD98 influences integrin function is not yet clear. CODS was predicated on the idea that it would identify integrin β cytoplasmic domain binding proteins (10.Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 370: 81-85Crossref Scopus (260) Google Scholar). Many β cytoplasmic domains manifest overall sequence similarity (1.Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (9026) Google Scholar, 2.Schwartz M.A. Schaller M.D. Ginsberg M.H. Annu. Rev. Cell Dev. Biol. 1995; 11: 549-599Crossref PubMed Scopus (1474) Google Scholar); however, the cytoskeletal protein, talin, binds to the muscle-specific splice variant, β1D, more tightly than to β1A. In addition, the leukocyte-specific β7 cytoplasmic domain binds to filamin more tightly than to β1A (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). We have now examined interactions between CD98 and recombinant parallel-dimerized integrin β1A, β1D, and β7 cytoplasmic domains by affinity chromatography (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). Here we report that CD98 interacts with the β1A but not β1D or β7 integrin cytoplasmic domains. Furthermore, the CD98 interaction is insensitive to β cytoplasmic domain mutations that abolish the binding of talin and filamin. The capacity of CD98 to complement dominant suppression correlates with its capacity to bind to the suppressive β cytoplasmic domains. The interaction of the integrin β1A cytoplasmic domain with CD98 may thus serve to regulate the localization and the function of these membrane proteins. The hybridoma cell line 4F2(C13) (anti-CD98) was purchased from American Type Culture Collection (ATCC). The CD98 antibody was purified from ascites produced in pristane-primed BALB/c mice by protein A affinity chromatography. Filamin antibody (monoclonal antibody 1680) was purchased from Chemicon and talin antibody (clone 8d4) from Sigma. Dr. S. Shattil (Scripps Research Institute) generously provided the activation-specific anti-αIIbβ3 monoclonal antibody, PAC1 (22.Shattil S.J. Hoxie J.A. Cunningham M. Brass L.F. J. Biol. Chem. 1985; 260: 11107-11114Abstract Full Text PDF PubMed Google Scholar). The anti-αIIbβ3 activating monoclonal antibody, anti-LIBS6, has been described previously (23.Frelinger III, A.L. Du X. Plow E.F. Ginsberg M.H. J. Biol. Chem. 1991; 266: 17106-17111Abstract Full Text PDF PubMed Google Scholar). The anti-Tac antibody, 7G7B6, was obtained from the American Tissue Culture Collection (Rockville, MD) and was biotinylated with biotin-N-hydroxysuccinimide (Sigma) according to manufacturer's instructions. The αIIbβ3-specific peptide inhibitor, Ro43-5054 (24.Alig L. Edenhofer A. Hadvary P. Hurzeler M. Knopp D. Muller M. Steiner B. Trzeciak A. Weller T. J. Med. Chem. 1992; 35: 4393-4407Crossref PubMed Scopus (202) Google Scholar), was a generous gift from B. Steiner (Hoffmann-La Roche, Basel, Switzerland). cDNA encoding the expressed integrin cytoplasmic domains joined to 4 heptad repeats (Fig. 1) were cloned into the modified pET-15 vector as described previously (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). Point mutations in β1D and β7 (Fig. 1) were performed utilizing the Quickchange kit (Stratagene). Recombinant expression in BL21 (DE3)pLysS cells (Novagen) and purification of the recombinant products were made in accordance with the manufacturers instructions (Novagen), with an additional final purification step on a reverse phase C18 high performance liquid chromatography column (Vydac). Polypeptide masses were confirmed by electrospray ionization mass spectrometry on an API-III quadrupole spectrometer (Sciex, Toronto, Ontario, Canada) and varied by less than 4 daltons from those predicted by the desired sequence. Tac-α5 and Tac-β1A DNA in modified CMV-IL2R expression vectors (25.LaFlamme S.E. Thomas L.A. Yamada S.S. Yamada K.M. J. Cell Biol. 1994; 126: 1287-1298Crossref PubMed Scopus (207) Google Scholar) were generously provided by Drs. S. LaFlamme and K. Yamada (National Institutes of Health, Bethesda, MD). Inserts encoding Tac-β1D, Tac-β7, Tac-β1A(Y788A), and Tac-β1A(801X) were subcloned into the modified CMV-IL2R expression vector asHindIII-XhoI fragments. αβpy cells, a Chinese hamster ovary cell line expressing the polyoma large T antigen and a constitutively active recombinant chimeric integrin, αIIbα6Aβ3β1(26.Baker E.K. Tozer E.C. Pfaff M. Shattil S.J. Loftus J.C. Ginsberg M.H. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1973-1978Crossref PubMed Scopus (67) Google Scholar), were maintained in Dulbecco's modified Eagle's medium (BioWhitaker); supplemented with 10% fetal calf serum (BioWhitaker), 1% non-essential amino acids (Life Technologies, Inc.), 1% glutamine (Sigma), 1% penicillin and streptomycin (Sigma), and 700 μg/ml G418 (Life Technologies, Inc.). Human Jurkat T cell lines were obtained from ATCC and maintained in RPMI1680 (BioWhitaker) supplemented with 10% fetal calf serum, 1% amino 1% and 1% penicillin and The cell line and a line D.J. 1992; PubMed Scopus Google Scholar) by T. were in Eagle's medium (BioWhitaker), supplemented with 10% fetal calf serum, 1% amino 1% and 1% penicillin and Jurkat cells were in and in according to the manufacturer's instructions were with and by on in A 1% and μg/ml and were as described previously (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). of Jurkat cells was performed The cells were in in and with a of with was to the and the was 4 The was and in a The cytoplasmic was and the membrane in a of and B. The membrane was in and and Recombinant proteins were expressed in cells (Novagen) and to (Novagen) through their in a of of of were with and 4 in an of were to cell in and and 4 and with A. of was to the and the was in a the was by and by In proteins were the with of and of 1% and was The proteins were 4 with an antibody to protein The the were with the and in were on and to were with and with or with specific and was with an kit of with recombinant proteins were by of of proteins. was performed as described previously (9.O'Toole T.E. Katagiri Y. Faull R.J. Peter K. Tamura R.N. Quaranta V. Loftus J.C. Shattil S.J. Ginsberg M.H. J. Cell Biol. 1994; 124: 1047-1059Crossref PubMed Scopus (581) Google Scholar). PAC1 binding was in a of αβpy cells Tac-α5 as by Integrin activation was as an activation as in which is the of PAC1 is the of PAC1 binding in the of is the of PAC1 binding in the of the integrin activating antibody of is as is the activation of cells with is the cells with CD98 and and is the of cells with The of have of and the Tac-β1D, and CD98 block integrin affinity by of β1A cytoplasmic a interaction between β1A and CD98 (10.Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 370: 81-85Crossref Scopus (260) Google Scholar). we examined the binding of membrane proteins to the β1A cytoplasmic affinity we used proteins in which the integrin cytoplasmic domain was joined to heptad repeats (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). The repeats form that the are and a Jurkat cell was to an affinity a cell of to the β1A but not to the was by the antibody, (Fig. on its mass and with antibody, the β1A binding was identified as the of CD98 binding to β integrin affinity chromatography was performed with β1D, and β7 cytoplasmic domains. CD98 not bind to β7 and binding to β1D was and (Fig. In talin and filamin (Fig. strongly to β1D and β7 as (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). CD98 to and binding was not by the of the cytoplasmic domain Thus, CD98 binding to integrin is integrin and CD98 binds to the β1A integrin cytoplasmic domain but not to those of β1D or The binding were performed and cell Thus, these CD98 binding to CD98 binding by or talin, which bind to β7 or β1D, (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). we used cells and cells D.J. 1992; PubMed Scopus Google Scholar) to the of in CD98 CD98 to the β1A but not of cells were used that is not CD98 binding to β1A. CD98 binding to β7 was not in the with not the of β7 to bind the of talin, we used cell membrane with a talin CD98 from these β1A but not β1D cytoplasmic domains (Fig. Thus, talin not CD98 binding to β1D, is it CD98 binding to β1A. The of β1A (Fig. 1) filamin and talin (Fig. binding (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). to mutations in β7 and β1D to the in β1A (Fig. filamin (Fig. 4 and talin (Fig. CD98 binding to β integrin was not by to mutations 4 and The to into β1D or β7 not CD98 was CD98 binding in the that talin or filamin not the of CD98 binding to β1D and β7 and that talin or filamin binding is not CD98 binding to the of isolated integrin β1A cytoplasmic in the form of a Tac-β1A in suppression of integrin activation. suppression is by of CD98 (10.Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 370: 81-85Crossref Scopus (260) Google Scholar). Tac-β1D, and dominant suppression of integrin activation (Fig. (Fig. CD98 to β1D and β7 that CD98 binding is not dominant suppression. CD98 was less the suppression by and (Fig. the capacity of CD98 to suppression correlates with its binding to the suppressive β cytoplasmic β1A integrin activation and bind CD98 binding is to dominant we first examined CD98 binding to a of β1A (Fig. CD98 binding was the were but not the amino acids were its capacity to bind to CD98, the Tac-β1A(801X) was a of integrin activation (Fig. and was not to a in the association of CD98 with (Fig. Furthermore, the which CD98 4 and to integrin activation (Fig. integrin β cytoplasmic domain binding to CD98 is not to dominant suppression. CD98 is implicated in several cellular amino acid cell fusion and integrin activation (12.Diaz Jr., L.A. Fox D.A. J. Biol. Reg. Homeostat. Agents. 1998; 12: 25-32PubMed Google Scholar). We previously that CD98 dominant suppression of integrin function (10.Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 370: 81-85Crossref Scopus (260) Google Scholar). We now report 1) CD98 associates with the β1A integrin cytoplasmic CD98 interacts with β cytoplasmic in a and splice which is of the capacity of the to bind the cytoskeletal proteins talin and capacity to associate with integrin correlates with its ability to dominant suppression of integrin CD98 association with integrin is dominant suppression of integrin activation. Thus, the association of CD98 with integrin cytoplasmic domains may regulate the function and localization of these membrane proteins. CD98 associates with β1A integrin cytoplasmic domains. association was utilizing protein of integrin cytoplasmic and it may the association of certain with The of the interaction was confirmed by the of binding to cytoplasmic domains from or several β CD98 was to the in the of cellular it that an protein is CD98 was the protein binding to the β1A (Fig. we CD98 binding in the of integrin binding talin and filamin and CD98 to bind to β1D and β7 cytoplasmic these bind of the as β1A (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). Thus, we that CD98 associates with the β1A and that the interaction is CD98 binds to integrin β cytoplasmic domains with unique splice variant and class specificity. CD98 to the and the to the β7 was The of CD98 binding from the of talin and filamin talin binds to the β1D and filamin to the β7 (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). the binding of cytoskeletal proteins is to the with in the first (21.Pfaff M. Liu S. Erle D.J. Ginsberg M.H. J. Biol. Chem. 1998; 273: 6104-6109Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar) in β1A as in β7 and CD98 binding was insensitive to although the of β1A were the were Thus, the of the β CD98 binding a integrin β CD98 binding to β correlates with its capacity to complement dominant suppression. CD98 was implicated in integrin activation by its capacity to reverse the suppression of integrin activation by an isolated β1A cytoplasmic domain (10.Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 370: 81-85Crossref Scopus (260) Google Scholar). In the we that CD98 binds to the β1A cytoplasmic domain, but to bind to the β7 or β1D cytoplasmic CD98 to complement dominant suppression by β7 or β1D cytoplasmic domains. the mechanism of CODS to CD98 binding to the suppressive β Furthermore, of CD98 integrin adhesion in cell cells (10.Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 370: 81-85Crossref Scopus (260) Google Scholar) and in certain cell lines C. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and cell fusion S. M. Ito M. M. A. A. Ito Y. J. 1998; PubMed Scopus Google Scholar, S. S. Nishio M. H. M. Komada H. Kawano M. Ito Y. J. Immunol. 1995; Google Scholar, S. S. M. Kawano M. Nishio M. K. Komada H. Ito Y. J. 1996; PubMed Scopus Google Scholar, K. S. Nishio M. M. Kawano M. Komada H. Ito M. Y. Ito Y. J. 1997; PubMed Scopus Google Scholar, K. M. S. Kawano M. Nishio M. Komada H. Ito M. Y. Ito Y. J. 1997; PubMed Scopus Google Scholar, S. M. Ito M. S. Nishio M. Kawano M. Komada H. M. Ito Y. Med. Immunol. 1997; PubMed Scopus Google Scholar, Ito M. K. S. S. M. Kawano M. H. Komada H. Nishio M. Ito Y. J. Immunol. 1994; Google Scholar, H. M. H. Y. S. Kawano M. S. Komada H. Nishio M. Ito Y. EMBO J. 1994; PubMed Scopus Google Scholar). Thus, that domain interactions with on integrin function is to involved in cell cell and of cell The interaction of CD98 with integrin cytoplasmic domains may involved in amino acid transport CD98 is to regulate and type amino acid transport (14.Kanai Y. Segawa H. Miyamoto K. Uchino H. Takeda E. Endou H. J. Biol. Chem. 1998; 273: 23629-23632Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar, 15.Torrents D. Estevez R. Pineda M. Fernandez E. Lloberas J. Shi Y.-B. Zorzano A. Palacin M. J. Biol. Chem. 1998; 273: 32437-32445Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 17.Mastroberardino L. Spindler B. Pfeiffer R. Loffing J. Skelley P.J. Shoemaker C.B. Verrey F. Nature. 1998; 395: 288-291Crossref PubMed Scopus (470) Google Scholar, 18.Pfeiffer R. Rossier G. Spindler B. Meier C. Kuhn L. Verrey F. EMBO J. 1999; 18: 49-57Crossref PubMed Scopus (239) Google Scholar). is to disulfide-bonded with a of light that resemble amino acid (13.Mannion B.A. Kolesnikova T.V. Lin S.W. Wang S. Thompson N.L. Hemler M.E. J. Biol. Chem. 1998; 273: 33127-33129Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 14.Kanai Y. Segawa H. Miyamoto K. Uchino H. Takeda E. Endou H. J. Biol. Chem. 1998; 273: 23629-23632Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar, 15.Torrents D. Estevez R. Pineda M. Fernandez E. Lloberas J. Shi Y.-B. Zorzano A. Palacin M. J. Biol. Chem. 1998; 273: 32437-32445Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 16.Estevez R. Camps M. Rojas A.M. Tesrar X. Deves R. Hediger M.A. Zorzano A. Palacin M. FASEB. 1998; 12: 1319-1329Crossref PubMed Scopus (72) Google Scholar, 17.Mastroberardino L. Spindler B. Pfeiffer R. Loffing J. Skelley P.J. Shoemaker C.B. Verrey F. Nature. 1998; 395: 288-291Crossref PubMed Scopus (470) Google Scholar, 18.Pfeiffer R. Rossier G. Spindler B. Meier C. Kuhn L. Verrey F. EMBO J. 1999; 18: 49-57Crossref PubMed Scopus (239) Google Scholar, 19.Pfeiffer R. Spindler B. Loffing J. Skelley P.J. Shoemaker C.B. Verrey F. FEBS Lett. 1998; 439: 157-162Crossref PubMed Scopus (90) Google Scholar, 20.Tsurudome M. Ito M. Takebayashi S. Okumura K. Nishio M. Kawano M. Kusawaga S. Komada S. Ito Y. J. Immunol. 1999; 162: 2462-2466PubMed Google Scholar). In mutations in of these light chains D. Estevez R. Pineda M. Fernandez E. Lloberas J. Shi Y.-B. Zorzano A. Palacin M. J. Biol. Chem. 1998; 273: 32437-32445Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar) are a of protein D. J. Pineda M. L. R. P. Zorzano A. V. K. A. P. Palacin M. 1999; PubMed Scopus Google Scholar). 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Thus, the of these cytoplasmic domains to bind to CD98 correlates with their of a in in or the association of CD98 with cytoplasmic domains may in the and of amino acid and to modulate the function of certain We their in the We Drs. Thomas and Shattil of the