The Kinase-null EphB6 Receptor Undergoes Transphosphorylation in a Complex with EphB1

Uniquely for the Eph family of receptor tyrosine kinases, the EphB6 receptor is catalytically inactive due to the alteration of several critical residues in its kinase domain. This has cast doubt upon its ability to participate in cytoplasmic signaling events. We show here that despite its lack of kinase activity, EphB6 undergoes inducible tyrosine phosphorylation upon stimulation with the Eph-B receptor subfamily ligand ephrin-B1. We also demonstrate, for the first time, evidence of cross-talk between Eph receptors. Overexpression of a catalytically active member of the Eph-B subfamily, EphB1, resulted in increased EphB6 phosphorylation. EphB1-induced EphB6 phosphorylation was ligand-dependent and required the functional catalytic activity of EphB1. EphB1 not only transphosphorylated EphB6, but together they also formed a stable hetero-complex. In addition, we identify the proto-oncogene c-Cbl as an EphB6-binding protein. Although EphB6-Cbl association appeared to be constitutive, Cbl required a functional phosphotyrosine binding domain in order to bind the receptor, whereas its RING finger motif ubiquitin-transfer domain was not necessary. Our findings demonstrate that EphB6 is an actively signaling receptor that undergoes transphosphorylation upon ligand binding and that can initiate specific cytoplasmic signaling events. Uniquely for the Eph family of receptor tyrosine kinases, the EphB6 receptor is catalytically inactive due to the alteration of several critical residues in its kinase domain. This has cast doubt upon its ability to participate in cytoplasmic signaling events. We show here that despite its lack of kinase activity, EphB6 undergoes inducible tyrosine phosphorylation upon stimulation with the Eph-B receptor subfamily ligand ephrin-B1. We also demonstrate, for the first time, evidence of cross-talk between Eph receptors. Overexpression of a catalytically active member of the Eph-B subfamily, EphB1, resulted in increased EphB6 phosphorylation. EphB1-induced EphB6 phosphorylation was ligand-dependent and required the functional catalytic activity of EphB1. EphB1 not only transphosphorylated EphB6, but together they also formed a stable hetero-complex. In addition, we identify the proto-oncogene c-Cbl as an EphB6-binding protein. Although EphB6-Cbl association appeared to be constitutive, Cbl required a functional phosphotyrosine binding domain in order to bind the receptor, whereas its RING finger motif ubiquitin-transfer domain was not necessary. 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Berg L.J. Oncogene. 1996; 13: 777-786PubMed Google Scholar, 39Matsuoka H. Iwata N. Ito M. Shimoyama M. Nagata A. Chihara K. Takai S. Matsui T. Biochem. Biophys. Res. Commun. 1997; 235: 487-492Crossref PubMed Scopus (50) Google Scholar). This lack of catalytic activity has cast doubt upon the ability of EphB6 to undergo tyrosine phosphorylation upon ligand stimulation and to initiate cytoplasmic signaling cascades. However, to draw an analogy with ErbB-3, a well characterized catalytically inactive member of the EGF receptor family (40Pinkas K.R. Soussan L. Waterman H. Levkowitz G. Alroy I. Klapper L. Lavi S. Seger R. Ratzkin B.J. Sela M. Yarden Y. EMBO J. 1996; 15: 2452-2467Crossref PubMed Scopus (691) Google Scholar), EphB6 may be transactivated by catalytically active Eph receptors and thus transduce intracellular signals. In this study, we demonstrate that the kinase-inactive EphB6 receptor undergoes tyrosine phosphorylation upon stimulation with membrane-bound ephrin-B1. EphB6 forms a hetero-receptor complex with co-expressed EphB1 receptor and undergoes transphosphorylation by the catalytically active EphB1 in a ligand-dependent manner. We also demonstrate that the EphB6 receptor associates with the c-Cbl oncogene. Cbl participates in the signaling pathways of many receptors, functioning as a regulator of receptor activity and binding a variety of signal-transducing molecules (41Fournel M. Davidson D. Weil R. Veillette A. J. Exp. Med. 1996; 183: 301-306Crossref PubMed Scopus (123) Google Scholar, 42Lupher Jr., M.L. S. H. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., M.L. Z. Shoelson S.E. H. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., M.L. N. C.E. S. B. H. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Science. 1997; PubMed Scopus Google Scholar, C.B. D.D. J. 1999; Google Scholar, S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar, Y. D.D. EMBO J. 1999; PubMed Scopus Google Scholar, G. Waterman H. E. Z. S. L. B. Yarden Y. Genes Dev. 1998; PubMed Scopus Google Scholar, S. Jr., M.L. B. H. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). Cbl induces of the and receptors Y. D.D. EMBO J. 1999; PubMed Scopus Google Scholar, G. Waterman H. E. Z. S. L. B. Yarden Y. Genes Dev. 1998; PubMed Scopus Google Scholar, S. P. H. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Cell. Biochem. 1999; 72: PubMed Scopus Google Scholar), an ability its RING finger domain H. Levkowitz G. Alroy I. Yarden Y. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Cbl binding to EphB6 was to be constitutive, and containing a RING finger bound EphB6 In binding was upon the of a Cbl of This the function of the Cbl a domain that is also crucial for interaction with receptor tyrosine kinases D.P. S. Jr., M.L. H. Mol. Cell. Biol. 1997; 17: PubMed Google Scholar). was to EphB6, and EphB1 and EphB6 receptors was for EphB1, EphB6, and by into the and of Cbl and to and EphB1 of to the required changes as the The and for Cbl The of the receptor was with the was by lysine to The resulting and to the of EphB6 and of the EphB1 receptor by of a and by of proteins and was by in cells and with in kinase the and forms of EphB1 active kinases not and cells the The to the cells for in the of the of to the proteins for stimulation with membrane-bound forms of the ephrin cells and they on a of or for the cells in was The was with to form was as a necessary. Although was this EphB6 phosphorylation. in of and on for was by for and of to and with for by a and to in the of on and to with in in with and with bound or and EphB receptors are by membrane-bound highly degenerate specificity with and most EphB receptors. the catalytically inactive EphB6 receptor be in to ligand we expressed EphB6 in cells and the cells to ephrin-B1. cell we cells with containing either or Ligand was by analysis not in cells or several cell not cells on cells with or and for The EphB6 receptor was with and with Stimulation of EphB6 with cells resulted in a in EphB6 tyrosine whereas with or cells The in EphB6 tyrosine phosphorylation upon with cells was also in and that the was not EphB6 tyrosine phosphorylation was detectable within of and increased The required to EphB6 phosphorylation was due to the in the of cell-cell contact the cells the EphB6 phosphorylation was upon ligand as of of EphB6 phosphorylation In to of which Eph receptor or forms can receptor autophosphorylation and signaling (19Davis S. Gale N.W. Aldrich T.H. Maisonpierre P.C. Lhotak V. Pawson T. Goldfarb M. Yancopoulos G.D. Science. 1994; 266: 816-819Crossref PubMed Scopus (627) Google Scholar, 20Sakano S. Serizawa R. Inada T. Iwama A. Itoh A. Kato C. Shimizu Y. Shinkai F. Shimizu R. Kondo S. Ohno M. Suda T. Oncogene. 1996; 13: 813-822PubMed Google Scholar). was also to EphB6 phosphorylation Although was for this this EphB6 phosphorylation as as the in The of EphB6 phosphorylation by be by the to the of a form of the EphB6 receptor extracellular domain the of a interaction between and EphB6 receptors. EphB6 is catalytically the tyrosine phosphorylation upon stimulation must the activity of an tyrosine an analogy with the catalytically inactive receptor of the family, EphB6 may be transphosphorylated by catalytically active members of the Eph this we co-expressed EphB6 with the EphB1 receptor in cells a of EphB1 However, EphB1 was to as with the receptor B. VandenBos T. Cerretti D.P. U. Strebhardt K. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, B. B. T. S. H. Strebhardt K. Oncogene. 1998; 17: PubMed Scopus Google Scholar). co-expressed with EphB1, EphB6 to undergo tyrosine in a to the EGF family receptor catalytically active EphB1 EphB6 phosphorylation as was upon EphB6 with a EphB1 In the activity of EphB1 was to be in or EphB6 transphosphorylation by EphB1 in a ligand-dependent The ability of EphB1 to EphB6 phosphorylation that the receptors be EphB6 and EphB1 be cells the of a interaction between the receptors and the formation of a stable this that the catalytically active EphB1 receptor The of EphB1 and EphB6, with their the that the phosphorylation of EphB6 upon EphB1 be due to of EphB1. between the receptors, we a EphB1 receptor residues but with its kinase domain The receptor was to the EphB1 but to of the EphB1 receptor, of the EphB1 also increased EphB6 phosphorylation in a and In these findings that EphB6 form hetero-receptor with an active Eph receptor and undergo transphosphorylation by the also that EphB6 phosphorylation in the of EphB1 may transphosphorylation by active Eph receptors. Cbl participates in the signaling pathways of many receptors, functioning as a regulator of receptor activity through the of receptor and binding a variety of signal-transducing molecules (41Fournel M. Davidson D. Weil R. Veillette A. J. Exp. Med. 1996; 183: 301-306Crossref PubMed Scopus (123) Google Scholar, 42Lupher Jr., M.L. S. H. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., M.L. Z. Shoelson S.E. H. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., M.L. N. C.E. S. B. H. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Science. 1997; PubMed Scopus Google Scholar, C.B. D.D. J. 1999; Google Scholar, S. J. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar, Y. D.D. EMBO J. 1999; PubMed Scopus Google Scholar, G. Waterman H. E. Z. S. L. B. Yarden Y. Genes Dev. 1998; PubMed Scopus Google Scholar, S. Jr., M.L. B. H. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). The ability of Cbl to with a variety of tyrosine kinase receptors to Eph receptors also bind We co-expressed the EphB6 and EphB1 receptors in cells with c-Cbl and their to Although we not association between Cbl and the catalytically active EphB1 receptor, Cbl with EphB6 This association appeared to be stimulation with cells the of EphB6-Cbl association the tyrosine phosphorylation of Cbl Although cells association with EphB6 only be upon of Cbl and the receptor, to receptor tyrosine further the we the binding of well characterized of Cbl to the EphB6 The was identified as a in the Cbl G.D. 1995; PubMed Google Scholar), which of Cbl binding to the and receptors D.P. S. Jr., M.L. H. Mol. Cell. Biol. 1997; 17: PubMed Google Scholar, C.B. Oncogene. 1997; 14: PubMed Scopus Google Scholar). The the function of the domain of through which tyrosine The Cbl was first as an a cell M. Oncogene. 1991; Google Scholar). Cbl an in the RING finger domain of In the upon Cbl binding to the EphB6 receptor, whereas the association association appeared to be constitutive, to be upon the Cbl domain and upon tyrosine phosphorylation of either the EphB6 receptor or an Although the structure of EphB6 is typical of the EphB receptors, its kinase domain alterations to critical catalytic and EphB6 kinase activity (38Gurniak C.B. Berg L.J. Oncogene. 1996; 13: 777-786PubMed Google Scholar, 39Matsuoka H. Iwata N. Ito M. Shimoyama M. Nagata A. Chihara K. Takai S. Matsui T. Biochem. Biophys. Res. Commun. 1997; 235: 487-492Crossref PubMed Scopus (50) Google Scholar). We that despite these structural the EphB6 receptor to stimulation by tyrosine phosphorylation. In addition, we show that this EphB6 tyrosine phosphorylation can be by a catalytically active Eph receptor, in by EphB1. EphB1 receptor transphosphorylation of EphB6 was in EphB6 may with members of the EphB subfamily in The ability to EphB1 and EphB6 that transphosphorylation as the of the formation of an Eph receptor complex on the catalytic activity, EphB6 is to as an receptor but as of a signaling complex with active EphB receptors in of the EGF receptor family has the only of a transphosphorylated kinase-inactive receptor (40Pinkas K.R. Soussan L. Waterman H. Levkowitz G. Alroy I. Klapper L. Lavi S. Seger R. Ratzkin B.J. Sela M. Yarden Y. EMBO J. 1996; 15: 2452-2467Crossref PubMed Scopus (691) Google however, findings that this may be a for signaling through catalytically inactive receptor tyrosine The receptor to the and of signaling by its active (40Pinkas K.R. Soussan L. Waterman H. Levkowitz G. Alroy I. Klapper L. Lavi S. Seger R. Ratzkin B.J. Sela M. Yarden Y. EMBO J. 1996; 15: 2452-2467Crossref PubMed Scopus (691) Google Scholar, G. Waterman H. E. Z. S. L. B. Yarden Y. Genes Dev. 1998; PubMed Scopus Google Scholar), and transphosphorylation results in the of and to the receptor J.G. J. Biol. 1994; Full Text PDF PubMed Google Scholar, H. Alroy I. S. Seger R. Yarden Y. EMBO J. 1999; PubMed Scopus Google Scholar). In a the catalytically inactive EphB6 receptor may specific cytoplasmic signaling molecules and thus cell by In to specific signaling pathways upon the catalytically inactive receptor is known to the of family as EphB receptors are by the is highly that they are in functional cross-talk with EphB6, EphB6 signaling through transphosphorylation and in EphB6, to the and receptors, was to with The of the C. Cbl interaction with the G.D. 1995; PubMed Google Scholar), and the Cbl binding to and receptors D.P. S. Jr., M.L. H. Mol. Cell. Biol. 1997; 17: PubMed Google Scholar, C.B. Oncogene. 1997; 14: PubMed Scopus Google Scholar). This also Cbl association with The the Cbl that EphB6 phosphorylation may be for Cbl we not binding of Cbl to EphB6 despite increased receptor tyrosine phosphorylation. However, was in that detectable of EphB6 phosphorylation that the Cbl binding of EphB6 be Cbl binding may be through a protein. This Cbl binding to a catalytically inactive of the G. Waterman H. E. Z. S. L. B. Yarden Y. Genes Dev. 1998; PubMed Scopus Google and the association of Cbl and EphB6 in Although EGF stimulation of the receptor induces tyrosine phosphorylation of Cbl G. Klapper E. A. Sela M. Yarden Y. Oncogene. 1996; Google Scholar), we not increased Cbl phosphorylation upon stimulation of EphB6 This lack of Cbl phosphorylation the of EphB6 catalytic activity, that EphB6 may Cbl to the cell and into Eph receptor its function through phosphorylation. The of inducible Cbl phosphorylation also that is not a of the catalytically active EphB6 Cbl is known to with of and of Cbl to sites of cell-cell contact by Eph receptors be for the regulation of cell-cell The ability of Cbl to bind EphB6 also the that EphB6 may be by It is that Cbl is for the of many receptors through the of receptor Y. D.D. EMBO J. 1999; PubMed Scopus Google Scholar, G. Waterman H. E. Z. S. L. B. Yarden Y. Genes Dev. 1998; PubMed Scopus Google Scholar, S. Jr., M.L. B. H. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). The of to the lysine residues of a for either in cytoplasmic or in the A. A. Annu. Rev. Biochem. 1998; PubMed Scopus Google Scholar). Cbl binding induces of the and receptors Y. D.D. EMBO J. 1999; PubMed Scopus Google Scholar, G. Waterman H. E. Z. S. L. B. Yarden Y. Genes Dev. 1998; PubMed Scopus Google Scholar, S. P. H. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Cell. Biochem. 1999; 72: PubMed Scopus Google Scholar), an ability its RING finger domain H. Levkowitz G. Alroy I. Yarden Y. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). As receptors binding to Cbl undergo is that EphB6 is In we that despite its lack of kinase activity, EphB6 is an actively signaling receptor that undergoes transphosphorylation and specific cytoplasmic signaling events. we also for the first time, evidence of cross-talk between members of the Eph receptor family, the of the Eph receptor signaling and the in to a We for

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