RYK, a Catalytically Inactive Receptor Tyrosine Kinase, Associates with EphB2 and EphB3 but Does Not Interact with AF-6

RYK is an atypical orphan receptor tyrosine kinase that lacks detectable kinase activity. Nevertheless, using a chimeric receptor approach, we previously found that RYK can signal via the mitogen-activated protein kinase pathway. Recently, it has been shown that murine Ryk can bind to and be phosphorylated by the ephrin receptors EphB2 and EphB3. In this study, we show that human RYK associates with EphB2 and EphB3 but is not phosphorylated by them. This association requires both the extracellular and cytoplasmic domains of RYK and is not dependent on activation of the Eph receptors. It was also previously shown that AF-6 (afadin), a PDZ domain-containing protein, associates with murine Ryk. We show here that AF-6 does not bind to human RYK in vitroor in vivo. This suggests that there are significant functional differences between human and murine RYK. Further studies are required to determine whether RYK modulates the signaling of EphB2 and EphB3. RYK is an atypical orphan receptor tyrosine kinase that lacks detectable kinase activity. Nevertheless, using a chimeric receptor approach, we previously found that RYK can signal via the mitogen-activated protein kinase pathway. Recently, it has been shown that murine Ryk can bind to and be phosphorylated by the ephrin receptors EphB2 and EphB3. In this study, we show that human RYK associates with EphB2 and EphB3 but is not phosphorylated by them. This association requires both the extracellular and cytoplasmic domains of RYK and is not dependent on activation of the Eph receptors. It was also previously shown that AF-6 (afadin), a PDZ domain-containing protein, associates with murine Ryk. We show here that AF-6 does not bind to human RYK in vitroor in vivo. This suggests that there are significant functional differences between human and murine RYK. Further studies are required to determine whether RYK modulates the signaling of EphB2 and EphB3. receptor tyrosine kinase nerve growth factor epidermal growth factor receptor platelet-derived growth factor green fluorescent protein hemagglutinin RYK is an atypical orphan receptor tyrosine kinase that differs from other members of this family at a number of conserved residues in the activation and nucleotide-binding domains and lacks detectable catalytic activity (1Hovens C.M. Stacker S.A. Andres A.C. Harpur A.G. Ziemiecki A. Wilks A.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11818-11822Crossref PubMed Scopus (115) Google Scholar, 2Katso R.M. Russell R.B. Ganesan T.S. Mol. Cell. Biol. 1999; 19: 6427-6440Crossref PubMed Scopus (62) Google Scholar, 3Wang X.C. Katso R. Butler R. Hanby A.M. Poulsom R. Jones T. Sheer D. Ganesan T.S. Mol. Med. 1996; 2: 189-203Crossref PubMed Google Scholar, 4Tamagnone L. Partanen J. Armstrong E. Lasota J. Ohgami K. Tazunoki T. LaForgia S. Huebner K. Alitalo K. Oncogene. 1993; 8: 2009-2014PubMed Google Scholar). The extracellular domain of RYK is quite short when compared with other RTKs,1 being only 183 amino acids long. It appears to be largely devoid of features characteristic of other RTKs, such as immunoglobulin-like domains (5Williams A. Barclay A. Annu. Rev. Immunol. 1988; 6: 381-405Crossref PubMed Scopus (1785) Google Scholar), fibronectin type III repeats (6Petersen T. Thogersen H. Skorstengaard K. Vibe-Pedersen K. Sahl P. Sottrup-Jensen L. Magnusson S. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 137-141Crossref PubMed Scopus (262) Google Scholar), or cysteine-rich domains (7Ullrich A. Coussens L. Hayflick J. Dull T. Gray A. Tam A. Lee J. Yarden Y. Libermann T. Schlessinger J. Nature. 1984; 309: 418-425Crossref PubMed Scopus (1991) Google Scholar). However, it contains two leucine-rich motifs that are usually implicated in highly specific protein/protein interactions (8Schneider R. Schneider-Scherzer E. Thurnher M. Auer B. Schweiger M. EMBO J. 1988; 7: 4151-4156Crossref PubMed Scopus (62) Google Scholar, 9Schneider R. Schweiger M. Oncogene. 1991; 6: 1807-1811PubMed Google Scholar) as well as in cell adhesion (10Rothberg J. Jacobs J. Goodman C. Artavanis-Tsakonas S. Genes Dev. 1990; 4: 2169-2187Crossref PubMed Scopus (433) Google Scholar). There is also a tetrabasic protease cleavage site (KRRK) flanked by two cysteine residues in the extracellular domain that is predicted to give rise to two fragments. Another interesting feature in the extracellular domain of RYK is the presence of a WIF (Wnt inhibitoryfactor) module (11Patthy L. Trends Biochem. Sci. 2000; 25: 12-13Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar), suggesting the possibility that RYK may bind to one of the members of the Wnt family of proteins. The ability of RYK to signal downstream was investigated using a chimeric receptor approach (2Katso R.M. Russell R.B. Ganesan T.S. Mol. Cell. Biol. 1999; 19: 6427-6440Crossref PubMed Scopus (62) Google Scholar). This conclusively demonstrated that the catalytic domain of RYK is inactive and that the amino acid alterations in the activation domain contribute to the lack of catalytic function. However, a tyrosine-phosphorylated 75-kDa protein was co-immunoprecipitated with the receptor, independently of stimulation, and activation of the mitogen-activated protein kinase pathway was observed following stimulation of the receptor. Interestingly, when the invariant lysine in subdomain II of the catalytic domain was mutated to alanine (K334A), abolishing any existing kinase activity, the receptor failed to activate the mitogen-activated protein kinase pathway and to bind and/or phosphorylate the 75-kDa protein. Further, RYK is overexpressed in ovarian tumors, and this correlates adversely with survival (12Katso R.M. Manek S. Ganjavi H. Biddolph S. Charnock M.F. Bradburn M. Wells M. Ganesan T.S. Clin. Cancer Res. 2000; 6: 3271-3281PubMed Google Scholar). The exact function of RYK is unknown, and its ligand has not been identified. A mouse model, where Ryk was homozygously deleted by homologous recombination, revealed an unusual, completely penetrant phenotype (13Halford M.M. Armes J. Buchert M. Meskenaite V. Grail D. Hibbs M.L. Wilks A.F. Farlie P.G. Newgreen D.F. Hovens C.M. Stacker S.A. Nat. Genet. 2000; 25: 414-418Crossref PubMed Scopus (144) Google Scholar). The mice were small, compared with wild type, and died within a week because of cleft palate. Such a phenotype has been found in other knockout mice, including those lacking members of the Ephrin receptor family (14Orioli D. Henkemeyer M. Lemke G. Klein R. Pawson T. EMBO J. 1996; 15: 6035-6049Crossref PubMed Scopus (287) Google Scholar). It was recently shown that although Ryk cannot autophosphorylate, it can associate and be phosphorylated by two members of the Eph family of receptors: EphB2 and EphB3 (13Halford M.M. Armes J. Buchert M. Meskenaite V. Grail D. Hibbs M.L. Wilks A.F. Farlie P.G. Newgreen D.F. Hovens C.M. Stacker S.A. Nat. Genet. 2000; 25: 414-418Crossref PubMed Scopus (144) Google Scholar). The Ephrin receptor family, which consists of 14 members, has been shown to mediate contact-dependent cell interactions that regulate the repulsion and adhesion mechanisms involved in the cell guidance and assembly of multicellular structures (15Holder N. Klein R. Development. 1999; 126: 2033-2044Crossref PubMed Google Scholar, 16Feng G.P. Laskowski M.B. Feldheim D.A. Wang H.M. Lewis R. Frisen J. Flanagan J.G. Sanes J.R. Neuron. 2000; 25: 295-306Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). They are important in the development of a range of vertebrate species, in the formation of blood vessels, axonal guidance, and metastasis of transformed cells (15Holder N. Klein R. Development. 1999; 126: 2033-2044Crossref PubMed Google Scholar, 17Tessier-Lavigne M. Cell. 1995; 82: 345-348Abstract Full Text PDF PubMed Scopus (185) Google Scholar). Yeast two-hybrid analysis, using the cytoplasmic domain of murine Ryk as a probe, has identified an interaction with AF-6, a PDZ domain-containing protein (13Halford M.M. Armes J. Buchert M. Meskenaite V. Grail D. Hibbs M.L. Wilks A.F. Farlie P.G. Newgreen D.F. Hovens C.M. Stacker S.A. Nat. Genet. 2000; 25: 414-418Crossref PubMed Scopus (144) Google Scholar). This interaction involved the PDZ domain of AF-6 and the C-terminal region of Ryk, especially the critical C-terminal valine residue. This valine residue is completely conserved among RYK homologues from Drosophila to human. AF-6 is a scaffold protein found at sites of cell-cell contact and a target of the Ras family of proteins (18Linnemann T. Geyer M. Jaitner B.K. Block C. Kalbitzer H.R. Wittinghofer A. Herrmann C. J. Biol. Chem. 1999; 274: 13556-13562Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 19Kuriyama M. Harada N. Kuroda S. Yamamoto T. Nakafuku M. Iwamatsu A. Yamamoto D. Prasad R. Croce C. Canaani E. Kaibuchi K. J. Biol. Chem. 1996; 271: 607-610Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Interestingly, a subset of activated Eph receptors, including EphB2, EphB3, and EphA7, also bind to AF-6 (20Hock B. Bohme B. Karn T. Yamamoto T. Kaibuchi K. Holtrich U. Holland S. Pawson T. Rubsamen-Waigmann H. Strebhardt K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9779-9784Crossref PubMed Scopus (175) Google Scholar, 21Buchert M. Schneider S. Meskenaite V. Adams M.T. Canaani E. Baechi T. Moelling K. Hovens C.M. J. Cell Biol. 1999; 144: 361-371Crossref PubMed Scopus (163) Google Scholar). The purpose of this study was to investigate further the interactions between RYK and the Eph receptors and between RYK and AF-6. The following plasmids were received as gifts: Myc-AF-6 from Kozo Kaibuchi (Nara Institute of Science and Technology, IKOMA, Japan) (19Kuriyama M. Harada N. Kuroda S. Yamamoto T. Nakafuku M. Iwamatsu A. Yamamoto D. Prasad R. Croce C. Canaani E. Kaibuchi K. J. Biol. Chem. 1996; 271: 607-610Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), HA.EphB3 and HA.EphB3K665R from Steven Stacker (Ludwig Institute for Cancer Research, Victoria, Australia) (21Buchert M. Schneider S. Meskenaite V. Adams M.T. Canaani E. Baechi T. Moelling K. Hovens C.M. J. Cell Biol. 1999; 144: 361-371Crossref PubMed Scopus (163) Google Scholar), and EphB2 from Tony Pawson (Samuel Lunenfeld Research Institute, Toronto, Canada) (22Holland S.J. Gale N.W. Mbamalu G. Yancopoulos G.D. Henkemeyer M. Pawson T. Nature. 1996; 383: 722-725Crossref PubMed Scopus (458) Google Scholar, 23Henkemeyer M. Marengere L.E. McGlade J. Olivier J.P. Conlon R.A. Holmyard D.P. Letwin K. Pawson T. Oncogene. 1994; 9: 1001-1014PubMed Google Scholar). The TrkA-RYK chimeric construct has been described previously (2Katso R.M. Russell R.B. Ganesan T.S. Mol. Cell. Biol. 1999; 19: 6427-6440Crossref PubMed Scopus (62) Google Scholar). The RYK.V5 plasmid was constructed by cloning RYK (GenBankTM accession number NM002958) in pTracer (Invitrogen) in frame with the V5 tag. A site was at the of the and the was mutated to by using the The construct was by cloning an accession number NM002958) in frame with in The human was from The was a from U. the Ryk was a from Steven Stacker (Ludwig Institute for Cancer M.M. A.C. Hibbs M.L. Wilks A.F. Stacker S.A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), and the RYK was the C-terminal region of RYK R.M. Manek S. Biddolph S. R. Charnock M.F. Wells M. Ganesan T.S. Cancer Res. 1999; Google Scholar). The following are AF-6 EphB2 V5 mouse and cells were using to the RYK.V5 and HA.EphB3 or EphB2 were in the The cells were with a the cells were on for in a protease and a was to was by for at at The cell were with and protein or at of the were in and in the were by to and The were to the The and were in and for the studies with cells were with and for in The cells were with human for or being The catalytic domain of RYK number NM002958) was by using the following and from The was as in a in frame with a on the and in The cells were with a of of at and in and protease and at for the protein was on a for at in The was with and the protein was in The protein was using a a and at in HA.EphB3 was in cells and using an of RYK catalytic domain was to protein using an The were in and in kinase The proteins to the were in of kinase and at for They were in kinase and in The proteins were by and and was using the the kinase using RYK as a and RYK.V5 were in cells and using an and and The were in and in kinase HA.EphB3 was with or RYK.V5 in of kinase and at for The were in kinase and in The proteins were by and and was using the A AF-6 construct was in cells and using an The cell from cells was also with the The protein were in and of the RYK catalytic was of at the were in and in being by and of cells with a C-terminal by by an and with the identified two a of at of and and at The was by the and a C-terminal from The the extracellular domain of the receptor M.M. A.C. Hibbs M.L. Wilks A.F. Stacker S.A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), only the of and The lack the of the extracellular domain the It is that the receptor is at the tetrabasic protease cleavage site which the amino in a predicted protein of the of the the does not the and RYK has not been shown to catalytic activity, in on a using the protein or the catalytic domain on its in (1Hovens C.M. Stacker S.A. Andres A.C. Harpur A.G. Ziemiecki A. Wilks A.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11818-11822Crossref PubMed Scopus (115) Google Scholar, 4Tamagnone L. Partanen J. Armstrong E. Lasota J. Ohgami K. Tazunoki T. LaForgia S. Huebner K. Alitalo K. Oncogene. 1993; 8: 2009-2014PubMed Google Scholar) or in using a chimeric receptor approach (2Katso R.M. Russell R.B. Ganesan T.S. Mol. Cell. Biol. 1999; 19: 6427-6440Crossref PubMed Scopus (62) Google Scholar). We to study the ability of RYK to using a We the catalytic domain in a it in and it in using the protein that the catalytic domain of RYK is to a EphB3 was phosphorylated in the presence of We cells with RYK.V5 with HA.EphB3 or a of EphB3 (21Buchert M. Schneider S. Meskenaite V. Adams M.T. Canaani E. Baechi T. Moelling K. Hovens C.M. J. Cell Biol. 1999; 144: 361-371Crossref PubMed Scopus (163) Google Scholar). of RYK by the both wild type EphB3 and were This that EphB3 and RYK and that this association is not dependent on activation and of the Eph receptor. However, although the with RYK was demonstrated using not there was of RYK when it is with EphB3. further the ability of EphB3 to phosphorylate we an in kinase on proteins. cells were with or and proteins were using the in kinase was using EphB3 and RYK or AF-6, and was with EphB3 failed to phosphorylate RYK the AF-6 was phosphorylated and EphB3 was to phosphorylate the catalytic domain of RYK in kinase not kinase using RYK as a EphB3, and AF-6 were from cells using and in was using EphB3 as a kinase and RYK.V5 or AF-6 as a as described the of EphB3 and AF-6 when are in the kinase presence of RYK by the presence of AF-6 by the presence of EphB3 by the A where we EphB3 and RYK in cells and EphB3 the Interestingly, only the of RYK with EphB3, suggesting an of the extracellular domain of RYK for this We also investigated the interaction between RYK and EphB2 both receptors were in cells and EphB2 was only the of RYK was although it is that the was not because of A that EphB2 was activated but not phosphorylate RYK. This suggests to EphB3, the association between RYK and EphB2 is dependent on the extracellular domain of RYK and does not to the of RYK. investigate further the association between RYK and EphB3 and whether the extracellular domain of RYK is required for the interaction to we EphB3 and a TrkA-RYK chimeric receptor or EphB3 and as a The TrkA-RYK chimeric receptor contains the extracellular domain of the receptor, and the and domains of RYK (2Katso R.M. Russell R.B. Ganesan T.S. Mol. Cell. Biol. 1999; 19: 6427-6440Crossref PubMed Scopus (62) Google Scholar). is a protein, and TrkA-RYK is or on its of The chimeric receptor, lacking the extracellular domain of not associate with EphB3 We to whether the extracellular domain of RYK on its was to bind EphB3. We constructed a the and domains of RYK and it with EphB3 in cells The predicted of protein, with is the protein at on because of EphB3 was not associate with suggesting that the receptor is required for the interaction between RYK and EphB3. The C-terminal of RYK a for the of a PDZ domain The C-terminal tyrosine and valine residues are completely RYK is devoid of catalytic activity and PDZ domains not bind to phosphorylated amino acids J. A. A.C. PubMed Scopus Google Scholar, H. L. M. P. 1995; PubMed Scopus Google Scholar, E. M. A. M. Nature. 1995; PubMed Scopus Google Scholar), it is that RYK may signal via a PDZ domain-containing protein. PDZ domain-containing only AF-6 has been shown to bind such as EphB2 and EphB3. In the of (13Halford M.M. Armes J. Buchert M. Meskenaite V. Grail D. Hibbs M.L. Wilks A.F. Farlie P.G. Newgreen D.F. Hovens C.M. Stacker S.A. Nat. Genet. 2000; 25: 414-418Crossref PubMed Scopus (144) Google Scholar), we to whether AF-6 to RYK. the TrkA-RYK chimeric receptor, which contains the cytoplasmic domain of and AF-6 were in not whether AF-6 A and or the chimeric receptor and was EphB3, which was as a for the was with AF-6 The possibility that AF-6 may bind to RYK when the is was when association was observed stimulation of TrkA-RYK with not with RYK not be in because the has a for further whether there is interaction between the we the catalytic domain of RYK. AF-6 was from cells and with the the proteins were by and shown AF-6 does not bind in the presence of of the catalytic domain of RYK. RYK is a receptor tyrosine kinase that to a family of receptors that are devoid of catalytic activity M. PubMed Scopus Google Scholar). The of signaling by receptors is for Yarden Y. PubMed Scopus Google Scholar). We observed of the RYK protein in cells with and The are receptors, because are by the V5 and the specific to the extracellular The be to differences in the of the protein, although other because the and are not by the The which this is is a at of the RYK protein. It contains a cysteine that be to this in at a of protein the T. B. K. 1998; PubMed Scopus Google Scholar). There are also two residues in the that be to by a D.P. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). such in the RYK protein, the of RYK may not be by the The is not by the the extracellular domain and be a of the receptor, from the cleavage of the extracellular This cleavage is to at the tetrabasic protease cleavage site cleavage among cell including receptor tyrosine such as M. G. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), receptor J.R. M.F. Mol. Cell. Biol. 9: PubMed Scopus Google Scholar), H. P. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar, H. K. P. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), M. S. Mol. Cell. Biol. PubMed Scopus Google Scholar), or N. E. E. D. A. J. Cell Biol. 1996; PubMed Scopus Google Scholar). It to be a to receptors by signaling R. G. 1999; Google Scholar, J.P. R. B. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). only the RYK and not the with EphB3 and EphB2, it with other RTKs, the cleavage of RYK the receptor, by of the ligand or the of other receptors. The of to two is unusual, but it has been The and receptors been shown to independently of receptor stimulation, and of was observed stimulation with by not on receptor kinase activity, but of one of the receptors, or of a protein that the receptors, by a kinase was required to formation Y. J. Y. Yamamoto K. B. Mol. Cell. Biol. PubMed Scopus Google Scholar). The interaction between RYK and the Eph receptors is because RYK does not phosphorylated and may a from that of interactions RYK as an of EphB2 and EphB3 by of receptors, but by mice for receptors to that RYK and two Eph receptors may in vivo. RYK is required in development and of structures and the (13Halford M.M. Armes J. Buchert M. Meskenaite V. Grail D. Hibbs M.L. Wilks A.F. Farlie P.G. Newgreen D.F. Hovens C.M. Stacker S.A. Nat. Genet. 2000; 25: 414-418Crossref PubMed Scopus (144) Google Scholar). mice in EphB2 and EphB3 mice in of cleft but also show (14Orioli D. Henkemeyer M. Lemke G. Klein R. Pawson T. EMBO J. 1996; 15: 6035-6049Crossref PubMed Scopus (287) Google Scholar) that are of phenotype Development. 1996; Google Scholar, Nature. 1995; PubMed Scopus Google Scholar, Dev. 1999; 82: PubMed Scopus Google Scholar, S. Nature. 1999; PubMed Scopus Google Scholar) is one of the RYK homologous in RYK with the Eph receptors in EphB2 and EphB3 are to bind to ephrin and when with receptors, to a This has been observed in the family of for can bind to but does not activate the receptor when it is with R. M. Wang L. M. A. S. M. R. Yarden Y. M. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar, R. L. H. G. L. S. R. M. Yarden Y. EMBO J. 1996; 15: PubMed Scopus Google Scholar). RYK also signaling downstream of the Eph receptors by specific cytoplasmic proteins. that both the and extracellular domains of RYK are required for the interaction with EphB3. It has been observed in the family of that stimulation of the extracellular domains of the receptors to but not EMBO J. 2000; 19: PubMed Scopus Google Scholar). This suggests that the extracellular domain are required for as is the for RYK and the Eph receptors. We demonstrated in this study that the association between RYK and EphB2 or EphB3 does not in the of RYK. However, a study (13Halford M.M. Armes J. Buchert M. Meskenaite V. Grail D. Hibbs M.L. Wilks A.F. Farlie P.G. Newgreen D.F. Hovens C.M. Stacker S.A. Nat. Genet. 2000; 25: 414-418Crossref PubMed Scopus (144) Google Scholar) when the receptors are murine Ryk associates with and is phosphorylated by EphB2 and EphB3. In both were in cells with the EphB3 but we a human RYK the the murine Ryk. The ability of EphB3 to phosphorylate RYK not be in or in The between the human and murine is but that not signal in the The of a by a kinase has been observed in the of N. Oncogene. 1999; PubMed Scopus Google Scholar). can be phosphorylated by mitogen-activated protein human is suggesting differences in the and the of the protein. Further, using a murine Ryk the of a study (13Halford M.M. Armes J. Buchert M. Meskenaite V. Grail D. Hibbs M.L. Wilks A.F. Farlie P.G. Newgreen D.F. Hovens C.M. Stacker S.A. Nat. Genet. 2000; 25: 414-418Crossref PubMed Scopus (144) Google Scholar) were to show that AF-6, a PDZ domain-containing protein, with the receptor via its PDZ domain and that the C-terminal valine of Ryk was for this AF-6 is a Ras at sites of cell-cell (18Linnemann T. Geyer M. Jaitner B.K. Block C. Kalbitzer H.R. Wittinghofer A. Herrmann C. J. Biol. Chem. 1999; 274: 13556-13562Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 19Kuriyama M. Harada N. Kuroda S. Yamamoto T. Nakafuku M. Iwamatsu A. Yamamoto D. Prasad R. Croce C. Canaani E. Kaibuchi K. J. Biol. Chem. 1996; 271: 607-610Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar) and has been shown to bind to EphB2 and EphB3 (20Hock B. Bohme B. Karn T. Yamamoto T. Kaibuchi K. Holtrich U. Holland S. Pawson T. Rubsamen-Waigmann H. Strebhardt K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9779-9784Crossref PubMed Scopus (175) Google Scholar, 21Buchert M. Schneider S. Meskenaite V. Adams M.T. Canaani E. Baechi T. Moelling K. Hovens C.M. J. Cell Biol. 1999; 144: 361-371Crossref PubMed Scopus (163) Google Scholar). However, we were to show any interaction between the cytoplasmic domain of human RYK and AF-6. The using the TrkA-RYK to be to not with the using murine Ryk, although only the extracellular domain of RYK was from the receptor. The observed differences in the can only be as being to The C-terminal of the human and mouse receptors, which is the AF-6 are but only in the mouse also be required for the AF-6 to EphB2 and EphB3 only receptors are activated and phosphorylated (20Hock B. Bohme B. Karn T. Yamamoto T. Kaibuchi K. Holtrich U. Holland S. Pawson T. Rubsamen-Waigmann H. Strebhardt K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9779-9784Crossref PubMed Scopus (175) Google the C-terminal of the receptors is not the only feature for the interaction with AF-6. In that the human of although it to EphB2 and EphB3, is not phosphorylated by receptors. Further studies the by which RYK may signaling by EphB2 and EphB3 are We S. K. T. and U. for with plasmids and We the of from S. M. and C.

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