CD98hc (SLC3A2) Interaction with β1 Integrins Is Required for Transformation

CD98hc (SLC3A2) constitutively and specifically associates with β1 integrins and is highly expressed on the surface of human tumor cells irrespective of the tissue of origin. We have found here that expression of CD98hc promotes both anchorage- and serum-independent growth. This oncogenic activity is dependent on β1 integrin-mediated phosphoinositol 3-hydroxykinase stimulation and the level of surface expression of CD98hc. Using chimeras of CD98hc and the type II membrane protein CD69, we show that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82–87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumor promotion by integrins. These results explain how high expression of CD98hc in human cancers contributes to transformation; furthermore, the transmembrane association of CD98hc and β1 integrins may provide a new target for cancer therapy. CD98hc (SLC3A2) constitutively and specifically associates with β1 integrins and is highly expressed on the surface of human tumor cells irrespective of the tissue of origin. We have found here that expression of CD98hc promotes both anchorage- and serum-independent growth. This oncogenic activity is dependent on β1 integrin-mediated phosphoinositol 3-hydroxykinase stimulation and the level of surface expression of CD98hc. Using chimeras of CD98hc and the type II membrane protein CD69, we show that the transmembrane domain of CD98hc is necessary and sufficient for integrin association in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation. Amino acids 82–87 in the putative cytoplasmic/transmembrane region appear to be critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumor promotion by integrins. These results explain how high expression of CD98hc in human cancers contributes to transformation; furthermore, the transmembrane association of CD98hc and β1 integrins may provide a new target for cancer therapy. The CD98 family is composed of widely expressed cell-surface disulfide-linked 125-kDa heterodimeric membrane glycoproteins containing a common glycosylated 80-kDa heavy chain (CD98hc, 4F2hc, SLC3A2) and a group of ∼45-kDa light chains. Early studies of peripheral blood T lymphocytes implicated CD98hc in the regulation of cellular activation (1Haynes B.F. Hemler M.E. Mann D. Eisenbarth G. Shelhamer J. Mostowski H.S. Thomas C.A. Strominger J.L. Fauci A. J. Immunol. 1981; 126: 1409-1414PubMed Google Scholar). Although expressed at low levels on the surface of quiescent cells, CD98hc is rapidly up-regulated early in transition from G0 to G1 phase following cellular activation and remains at elevated levels until the cell cycle is complete (2Azzarone B. Malpiece Y. Zaech P. Moretta L. Fauci A. Suarez H. Exp. Cell Res. 1985; 159: 451-462Crossref PubMed Scopus (19) Google Scholar, 3Suomalainen H.A. J. Immunol. 1986; 137: 422-427PubMed Google Scholar, 4Parmacek M.S. Karpinski B.A. Gottesdiener K.M. Thompson C.B. Leiden J.M. Nucleic Acids Res. 1989; 17: 1915-1931Crossref PubMed Scopus (86) Google Scholar). All embryonic fibroblasts express CD98hc, and expression gradually diminishes on cells with maturity. CD98hc is highly expressed on the surface of tumor cells, irrespective of the tissue of origin (5Bellone G. Alloatti G. Levi R. Geuna M. Tetta C. Peruzzi L. Letarte M. Malavasi F. Eur. J. Immunol. 1989; 19: 1-8Crossref PubMed Scopus (26) Google Scholar, 6Dixon W.T. Sikora L.K. Demetrick D.J. Jerry L. M Int. J. Cancer. 1990; 45: 59-68Crossref PubMed Scopus (27) Google Scholar). Deletion of CD98hc in embryonic stem cells blocks their ability to form teratomas in mice, 1C. Feral and M. H. Ginsberg, submitted for publication. and overexpression of CD98hc in murine fibroblasts results in anchorage-independent growth (7Hara K. Kudoh H. Enomoto T. Hashimoto Y. Masuko T. Biochem. Biophys. Res. Commun. 1999; 262: 720-725Crossref PubMed Scopus (65) Google Scholar). In addition, increased CD98hc expression correlates with the development, progression, and metastatic potential of tumors (8Esteban F. Ruiz-Cabello F. Concha A. Perez Ayala M. Delgado M. Garrido F. Cancer. 1990; 66: 1493-1498Crossref PubMed Scopus (32) Google Scholar, 9Garber M.E. Troyanskaya O.G. Schluens K. Petersen S. Thaesler Z. Pacyna-Gengelbach M. van de Rijn M. Rosen G.D. Perou C.M. Whyte R.I. Altman R.B. Brown P.O. Botstein D. Petersen I. Proc. Natl. Acad. Sci. U. S. A. 2001; 98 (Correction (2002) Proc. Natl. Acad. Sci. U. S. A.99, 1098): 13784-13789Crossref PubMed Scopus (1103) Google Scholar, 10Yoon J.H. Kim Y.B. Kanai Y. Endou H. Kim K. Anticancer Res. 2003; 23: 3877-3881PubMed Google Scholar). Thus, CD98hc plays an important role in tumorigenesis; however, its mechanism of action has not been determined. The integrin family of cell-surface heterodimeric glycoproteins composed of α and β subunits function primarily as receptors for extracellular matrix ligands, which regulate many aspects of cell physiology, including morphology, adhesion, migration, proliferation, and differentiation (11Schwartz M.A. J. Cell Biol. 1997; 139: 575-578Crossref PubMed Scopus (305) Google Scholar). Many cancers show abnormalities of integrin function as a result of transformation by oncogenes (12Zou J.X. Liu Y. Pasquale E.B. Ruoslahti E. J. Biol. Chem. 2002; 277: 1824-1827Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). More importantly, the growth of several tumors depends on β1 integrin function (13Weaver V.M. Petersen O.W. Wang F. Larabell C.A. Briand P. Damsky C. amd Bissell M.J. J. Cell Biol. 1997; 137: 231-245Crossref PubMed Scopus (1205) Google Scholar). CD98hc constitutively and specifically associates with β1 integrins (14Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 390: 81-85Crossref PubMed Scopus (260) Google Scholar, 15Zent R. Fenczik C.A. Calderwood D.A. Liu S. Dellos M. Ginsberg M.H. J. Biol. Chem. 2000; 275: 5059-5064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 16Merlin D. Sitaraman S. Liu X. Eastburn K. Sun J. Kucharzik T. Lewis B. Madara J.L. J. Biol. Chem. 2001; 276: 39282-39289Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 17Miyamoto Y.J. Mitchell J.S. McIntyre B.W. Mol. Immunol. 2003; 390: 739-751Crossref Scopus (26) Google Scholar, 18Rintoul R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google and that CD98hc plays a role in integrin-mediated in cancer cells. CD98hc promotes activation of 3-hydroxykinase focal adhesion cell of focal adhesion R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google and K. K. T. M. T. M. 2001; PubMed Scopus Google and β1 integrin-mediated cell adhesion in a of cancer cells, including and cell cancer (14Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 390: 81-85Crossref PubMed Scopus (260) Google Scholar, S. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and of integrin on the surface of cells B.A. F. Hemler M.E. Biochem. 2001; PubMed Scopus Google Scholar). The mechanism by which CD98hc associates with and integrin function and role plays in transformation The extracellular domain of CD98hc with at light to form a of that in The role of the light chain in CD98hc with regulation of function of β1 integrins is of in CD98hc that association with the light chain and that the activity of CD98hc in cells T. S. M. T. Hashimoto Y. Enomoto T. Masuko T. Int. J. Cancer. 2000; PubMed Scopus Google and of β1 integrin association in low light chain membrane B.A. F. Hemler M.E. Biochem. 2001; PubMed Scopus Google Scholar). to in and integrin in cells R. Fenczik C.A. Calderwood D.A. Liu S. Dellos M. Ginsberg M.H. J. Biol. Chem. 2000; 275: 5059-5064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). of CD98hc by β1 is not the mechanism of R. Fenczik C.A. Calderwood D.A. Liu S. Dellos M. Ginsberg M.H. J. Biol. Chem. 2000; 275: 5059-5064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). In that the cytoplasmic/transmembrane domain of CD98hc is the critical region CD98hc of β1 integrin surface and in cells and of in cells R. Fenczik C.A. Calderwood D.A. Liu S. Dellos M. Ginsberg M.H. J. Biol. Chem. 2000; 275: 5059-5064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 16Merlin D. Sitaraman S. Liu X. Eastburn K. Sun J. Kucharzik T. Lewis B. Madara J.L. J. Biol. Chem. 2001; 276: 39282-39289Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). We have that CD98hc activity in a β1 R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google Scholar). The of to the mechanism by which overexpression of CD98hc to cellular in the and β1 integrins. We found that cellular transformation by overexpression of CD98hc depends on activation of by focal adhesion This activation depends on the of β1 integrins with CD98hc and is with of the integrins. we found that the CD98hc transmembrane domain is necessary and sufficient for integrin association and activation and transformation by CD98hc. This protein plays an important role in the of the CD98hc and that to transformation. by de The CD98hc chimeras by and acids of CD98hc acids of and acids of CD98hc. acids of and acids of CD98hc. acids of CD98hc and acids of acids of CD98hc and acids of acids of CD69, acids of CD98hc, and acids of acids of and acids of CD98hc. has a of acids which the domain of CD98hc, the as as the by D. and J. L. D. Sitaraman S. Liu X. Eastburn K. Sun J. Kucharzik T. Lewis B. Madara J.L. J. Biol. Chem. 2001; 276: 39282-39289Abstract Full Text Full Text PDF PubMed Scopus (49) Google has a of acids which the domain and the acids of the transmembrane The which The by the human a CD98 light a from F. of the following and protein and and integrin protein for of CD98hc and CD98hc chimeras containing the extracellular domain of CD98hc. for of and chimeras containing the extracellular domain of β1 β1 integrin for for and and for Cell and cells from the of Cell and in containing and The cell and have been R. M. J. S. R. R. J. Cell Biol. PubMed Scopus Google Scholar, T. R. D. J. Cell Biol. PubMed Scopus (96) Google Scholar). cells fibroblasts from β1 embryonic stem cells. The and cell from cells with the and murine integrin K. A. T. M. R. S. Mol. Biol. 2000; PubMed Scopus Google Scholar). cells in containing and and cells in the containing for of cell with following the a of at in cell cells with The cell from and in containing and by protein of Cell cells following the in for for the and in with from in and human CD98hc expression by cell for of cells and in of containing of CD98hc and chimeras containing the extracellular of of and chimeras containing the extracellular of for at by with with for at and with in and by and for and CD69, in in containing The cells a of in in in a of and at cells a light as a of the of cells that activity as R.C. C. Sethi T. Res. Google Scholar). cells in containing and from cell and for activity and as by by and by for of levels as J. Scholar). In cells to a and containing to in the of the group The of by from a protein a with and from in and with at in containing and and by for at of and in for of cell by The with of at of protein and with with on The to in and for at and with at for by to the Amino and in and containing and at for of containing to and for an at on and with of containing and The cells with of in for of to containing of and activity in a with and in in with and and the of CD98hc and β1 with at to In with of of the β1 with a and as of the of of studies on to and on the of CD98hc and the role that CD98hc plays in we the of human CD98hc in cells on anchorage-independent growth in a of transformation that correlates with growth in mice, human tumor and G. PubMed Scopus (27) Google Scholar, Res. Google Scholar). cell-surface levels of CD98hc cells as CD98hc, is a of the type II transmembrane protein the of and results In addition, results a with Furthermore, expression not β1 integrin expression as by not The of cells CD98hc that of cells. In addition, the of in the with the level of CD98hc cell-surface expression of the is the ability of cells to that CD98hc anchorage-independent growth is as an of transformation. In cell the CD98hc with cells in the of growth plays a role in integrin activation and cellular activation and transformation Cell Biol. PubMed Scopus Google Scholar). We the of CD98hc on activity in cells. of CD98hc increased activity with expression of by and increased of protein The Brown J. Biol. Chem. Full Text PDF PubMed Google a of the ability of cells CD98hc Thus, increased expression of CD98hc an and anchorage-independent growth. These dependent on the level of CD98hc cell-surface expression and by The Acids of CD98hc and for of and chimeras which the and of CD98hc with of the type II membrane protein as in cells to the of CD98hc to activation and transformation. cell at levels as by and The membrane of CD98hc and of the chimeras has been C.A. R. Dellos M. Calderwood D.A. J. C. Ginsberg M.H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google the is and the is expression not β1 integrin expression as by not of chimeras in cells. chimeras cells. The results from of expression in the The results from of expression of chimeras in Cell with as of expression of chimeras containing the extracellular domain as the The of chimeras on activity in cells both by in and by of the a J. Scholar). The transmembrane domain of CD98hc necessary and sufficient to and to levels and In the and and transmembrane and the which the domain acids is both to activation and of In the which the transmembrane domain of CD98hc is with the transmembrane domain of not activity The of expression on in and is in All cells the transmembrane domain of CD98hc with to of cells CD98hc. In chimeras containing the transmembrane domain of that not from of cells. In a CD98hc with the domain and the the transmembrane domain of CD98hc and the extracellular and of both expressed in cells and with cells of in the which the transmembrane domain of CD98hc is with the transmembrane not in not results a with and the of the transmembrane domain of CD98hc is necessary and sufficient to to and to anchorage-independent growth. The Acids of CD98hc and for CD98hc and β1 to the β1 integrins and CD98hc in We have that CD98hc constitutively associates with β1 of activation and integrin R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google Scholar). CD98hc and β1 integrin in the membrane by and β1 integrins in cells the for the CD98hc and β1 the following chimeras the transmembrane domain of CD98hc and the extracellular and of and has the domain acids by and expressed in cells, both with β1 integrins which that of β1 integrins with CD98hc, expressed in cells, the transmembrane domain of and the extracellular and of β1 integrin an to the association chimeras and β1 integrins by cells in and with integrin by and with CD98hc and the the with β1 integrins as by a CD98hc at and of In the the transmembrane domain of and the extracellular and of to with β1 integrins. Thus, chimeras containing the CD98hc transmembrane domain with β1 The in which with of and with integrin not with β1 CD98hc and the chimeras containing the transmembrane domain of CD98hc with β1 integrins. chimeras containing the transmembrane domain of that the transmembrane domain of CD98hc is necessary and sufficient for integrin Thus, as by in and the transmembrane domain of CD98hc its with β1 integrins. Furthermore, chimeras that and with β1 integrins activity and anchorage-independent that β1 integrin association is required for transformation. CD98hc β1 and integrin function (14Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 390: 81-85Crossref PubMed Scopus (260) Google Scholar). We to the of CD98hc and chimeras on the of β1 integrins and focal adhesion of CD98hc β1 integrin surface of peripheral for β1 integrins Furthermore, overexpression of CD98hc and focal adhesion with increased β1 integrin This by the which the transmembrane domain of CD98hc and the extracellular and of CD98hc β1 and plays a role in integrin of CD98hc a in the level of expression of the and and transmembrane sufficient to in cells from β1 embryonic cells cells β1 integrin and cells a β1 integrin with which have been to have a in β1 R. M. J. S. R. R. J. Cell Biol. PubMed Scopus Google Scholar, T. R. D. J. Cell Biol. PubMed Scopus (96) Google to the role of β1 integrins and in by the transmembrane domain of CD98hc. CD98hc, CD69, and the containing the transmembrane domain of CD98hc the cell of in cell β1 integrin and expression for cell as not R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google Scholar). CD98hc by activity an in of of by of with In the cells, overexpression of CD98hc a in R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google Scholar). The transmembrane domain of CD98hc sufficient to activity overexpression of CD98hc the the transmembrane domain of not activity in cells cells overexpression of CD98hc the a in growth in in however, overexpression of not growth in cells These results show that the transmembrane of CD98hc with β1 integrins is necessary for activation and anchorage-independent growth and a role for in the of activation on cells CD69, CD98hc, CD98hc chimeras with the D.A. D.A. J. 2002; PubMed Scopus Google Scholar). The the in activity by expression of CD98hc the containing the transmembrane domain of CD98hc that is required for Amino Acids of CD98hc for and Amino of CD98hc with β1 the The acids is expressed in cells as by and and Although the and the the putative acids to with β1 to and to anchorage-independent growth in and the to with β1 to activity expressed in cells, and not anchorage-independent growth in and to with the light chain and a in These results that acids at the putative domain required for integrin and transformation and show that of In we the CD98hc, integrin and transformation. We have the The heavy chain of CD98 promotes anchorage- and serum-independent growth in cells. This oncogenic activity is dependent on activation and the level of CD98hc cell-surface Using CD98hc we have that the transmembrane domain of CD98hc is necessary and sufficient for of activation of increased levels of and anchorage-independent growth. The transmembrane domain is necessary and sufficient for integrin Furthermore, chimeras that with β1 integrins activity and anchorage-independent growth. of human CD98hc β1 integrin surface and promotes focal adhesion The transmembrane domain of CD98hc is sufficient to The of β1 integrin and activation necessary for the transmembrane domain of CD98hc to Using of CD98hc, we results that the ability to transformation and integrin activation and in the putative cytoplasmic/transmembrane domain acids This CD98hc and β1 integrins to be critical for the oncogenic activity of CD98hc. CD98hc plays an important role in Deletion of CD98hc the of from embryonic stem and overexpression of CD98hc in cells to anchorage-independent growth and tumor in (7Hara K. Kudoh H. Enomoto T. Hashimoto Y. Masuko T. Biochem. Biophys. Res. Commun. 1999; 262: 720-725Crossref PubMed Scopus (65) Google Scholar). Furthermore, CD98hc promotes anchorage-independent growth in cell cancer cells R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google Scholar). The ability of cells to in is a of and of the with and of human tumors Res. Google Scholar). Full oncogenic transformation is to both and anchorage-independent growth (11Schwartz M.A. J. Cell Biol. 1997; 139: 575-578Crossref PubMed Scopus (305) Google Scholar). We have here that cells of both anchorage- and serum-independent that overexpression of CD98hc oncogenic transformation by that from both integrins and growth β1 integrins a role in cancer (13Weaver V.M. Petersen O.W. Wang F. Larabell C.A. Briand P. Damsky C. amd Bissell M.J. J. Cell Biol. 1997; 137: 231-245Crossref PubMed Scopus (1205) Google Scholar, S. 2001; PubMed Scopus Google Scholar). CD98hc associates with β1 integrins R. Fenczik C.A. Calderwood D.A. Liu S. Dellos M. Ginsberg M.H. J. Biol. Chem. 2000; 275: 5059-5064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 16Merlin D. Sitaraman S. Liu X. Eastburn K. Sun J. Kucharzik T. Lewis B. Madara J.L. J. Biol. Chem. 2001; 276: 39282-39289Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 17Miyamoto Y.J. Mitchell J.S. McIntyre B.W. Mol. Immunol. 2003; 390: 739-751Crossref Scopus (26) Google and we have that CD98hc results in R.C. Buttery R.C. D. C. Sethi T. Mol. Biol. 2002; PubMed Scopus Google Scholar). have been to CD98hc to β1 the may not be B.A. F. Hemler M.E. Biochem. 2001; PubMed Scopus Google Scholar). an of to the of the integrin In show that the and transmembrane of CD98hc both necessary and sufficient for to and for the of C.A. R. Dellos M. Calderwood D.A. J. C. Ginsberg M.H. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The results here show that chimeras that to β1 integrins integrin by and increased levels of and transformation. in which the putative transmembrane domain of CD98hc is with that of the to and with β1 to and to anchorage-independent growth. with of CD98hc that acids of the putative CD98hc region of the domain required for Although acids may integrin is that of acids may result in a in the CD98hc/β1 integrin results with and the of the CD98hc region of the domain in β1 integrin function and transformation. as and the membrane region S. Calderwood D.A. Ginsberg M.H. J. Cell Sci. 2000; PubMed Google and to the CD98hc may as a in the the association of integrins in the of the membrane with transmembrane from the and the of on integrin CD98hc expression is high on the surface of human tumor cells (5Bellone G. Alloatti G. Levi R. Geuna M. Tetta C. Peruzzi L. Letarte M. Malavasi F. Eur. J. Immunol. 1989; 19: 1-8Crossref PubMed Scopus (26) Google Scholar, 6Dixon W.T. Sikora L.K. Demetrick D.J. Jerry L. M Int. J. Cancer. 1990; 45: 59-68Crossref PubMed Scopus (27) Google Scholar). in cells, the expression of CD98hc not result in the of (7Hara K. Kudoh H. Enomoto T. Hashimoto Y. Masuko T. Biochem. Biophys. Res. Commun. 1999; 262: 720-725Crossref PubMed Scopus (65) Google have that levels of CD98hc in cells result in increased In we have that levels of CD98hc increased levels of integrin with and transformation. is up-regulated in a of human with expression to Furthermore, a expression and tumor in and has in to function as a in cancer E. 2003; PubMed Scopus Google Scholar, E. Res. 1999; PubMed Google Scholar). constitutively embryonic fibroblasts M. D. A. 1997; 276: PubMed Scopus Google and a of fibroblasts in C. A. E. S. C. J.L. L. E. M.A. J. A. I. J. 17: PubMed Scopus Google Scholar). In addition, protein has been to anchorage-independent growth R.C. C. Sethi T. Res. Google Scholar, A. P. S. J. J. 1997; PubMed Scopus Google Scholar). results that a mechanism by which CD98hc overexpression transformation in human cancers is an in integrin with β1 and The role of in transformation remains to be cells and cells have focal adhesion Furthermore, in not results T. R. D. J. Cell Biol. PubMed Scopus (96) Google cell on and focal adhesion and in and focal adhesion cells have and focal cells, cells have and focal Thus, results that plays a role in CD98hc/β1 integrin-mediated activation and remains that integrin-mediated activation blocks activation and transformation as a result of in focal adhesion The of CD98hc with light has been to regulate integrins B.A. F. Hemler M.E. Biochem. 2001; PubMed Scopus Google Scholar). CD98hc and E. M. H. F. M. K. S. A. K. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. H. K. H. E. Endou H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This regulation to be to with a of light E. M. H. F. M. K. S. A. K. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, L. B. R. J. C.B. F. Nature. PubMed Scopus Google Scholar). In to is a the heavy and light of CD98 R. B. J. C.B. PubMed Scopus Google Scholar). We CD98hc chimeras the CD98hc extracellular domain to the of with the light results show that integrin and stimulation of anchorage-independent growth by CD98hc and from the regulation of in which the transmembrane domain of CD98hc is with that of the to and with β1 to and to anchorage-independent growth. In on the function of CD98 not R. Fenczik C.A. Calderwood D.A. Liu S. Dellos M. Ginsberg M.H. J. Biol. Chem. 2000; 275: 5059-5064Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). of the extracellular domain of CD98hc with that of in a protein that of integrin function not These results that the association of CD98hc with a light chain is not required for its with integrins for the regulation of integrins. The CD98hc which blocks to the light has been to integrin association B.A. F. Hemler M.E. Biochem. 2001; PubMed Scopus Google Scholar). as of the extracellular domain of CD98hc function These that the of the on be to of light chain and may result from a in the of CD98hc. This is by the in CD98hc by the T. S. M. T. Hashimoto Y. Enomoto T. Masuko T. Int. J. Cancer. 2000; PubMed Scopus Google Scholar). CD98hc is highly expressed on the surface of tumor cells irrespective of the tissue of origin (5Bellone G. Alloatti G. Levi R. Geuna M. Tetta C. Peruzzi L. Letarte M. Malavasi F. Eur. J. Immunol. 1989; 19: 1-8Crossref PubMed Scopus (26) Google Scholar, 6Dixon W.T. Sikora L.K. Demetrick D.J. Jerry L. M Int. J. Cancer. 1990; 45: 59-68Crossref PubMed Scopus (27) Google Scholar). Many cancer cells show abnormalities of integrin function as a result of transformation by oncogenes (12Zou J.X. Liu Y. Pasquale E.B. Ruoslahti E. J. Biol. Chem. 2002; 277: 1824-1827Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). CD98hc integrin function in cancer cells. CD98hc integrin adhesion in cell cancer cells and cancer cell (14Fenczik C.A. Sethi T. Ramos J.W. Hughes P.E. Ginsberg M.H. Nature. 1997; 390: 81-85Crossref PubMed Scopus (260) Google Scholar, S. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). results that the the domain of CD98hc and β1 integrins to activation of the of integrin This the of in activation and transformation. have been in CD98hc to however, that its with integrins be to Furthermore, increased expression of CD98hc promotes overexpression of growth family by increased G.D. J.M. J.M. L. M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google has been implicated in a of human oncogenes as of the growth family in tumor In is increased expression of CD98hc on tumor cells (5Bellone G. Alloatti G. Levi R. Geuna M. Tetta C. Peruzzi L. Letarte M. Malavasi F. Eur. J. Immunol. 1989; 19: 1-8Crossref PubMed Scopus (26) Google Scholar, 6Dixon W.T. Sikora L.K. Demetrick D.J. Jerry L. M Int. J. Cancer. 1990; 45: 59-68Crossref PubMed Scopus (27) Google Scholar). the of transformation may in the oncogenic and may provide a novel target for cancer therapy. We of and for