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Address correspondence to W. Birchmeier, Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13092 Berlin, Germany. Tel.: (49) 309-406-3800. Fax: (49) 309-406-2656. E-mail: wbirch{at}mdc-berlin.de
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Abstract |
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Key Words: signal transduction; yeast two-hybrid system; docking proteins; neural development; endothelia
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Introduction |
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The specificity of receptor tyrosine kinase signaling has been investigated in great detail. A variety of substrates are shared by several receptors (Ullrich and Schlessinger, 1990; van der Geer et al., 1994). In addition, specific docking proteins of receptor tyrosine kinases have been discovered which mediate particular biological responses. Insulin receptor substrate (IRS)-1 and IRS-2 are two essential substrates of the insulin receptor and, accordingly, ablation of the IRS-2 gene in mice results in diabetes (Sun et al., 1991, 1995; Withers et al., 1998). Gab1 is important for signaling of c-Met; Gab-1deficient mice exhibit a phenotype similar to c-Met-/- mice, i.e., embryonal lethality and impaired migration of myogenic precursor cells (Bladt et al., 1995; Weidner et al., 1996; Sachs et al., 2000). Moreover, FRS2 mediates FGF and Trk receptor signaling in cells (Kouhara et al., 1997; Meakin et al., 1999). Similarly, dos in Drosophila is essential in sevenless signaling (Herbst et al., 1996; Raabe et al., 1996). These docking proteins contain NH2-terminal membrane-targeting elements, pleckstrin homology (PH) domains or myristylation sites, and receptor-targeting sequences, PTB or PTB-like domains. In addition, docking proteins harbor multiple consensus binding sites for SH2 and SH3 containing molecules.
Several recent reports implicate the previously identified dok members, p62dok (dok-1), dok-2, and dok-3, in negative regulation of signaling pathways activated by tyrosine kinases. These doks inhibit mitogen-activated protein (MAP) kinase signaling, cell proliferation, and cellular transformation (Cong et al., 1999; Suzu et al., 2000; Tamir et al., 2000). The closely related p62dok and dok-2 may exert their inhibitory effects by recruitment of rasGAP, a negative regulator of ras signaling. Dok-2 can also attenuate EGF receptor (EGFR)-induced MAP kinase activation, independent of its association with rasGAP (Jones and Dumont, 1999). Also, dok-3 is a negative regulator of immune receptor and v-Abl signaling without binding rasGAP, but recruiting SHIP and Csk (Cong et al., 1999; Lemay et al., 2000). The p62dok family members resemble docking proteins in their structure, since they contain PH and PTB domains as well as multiple SH2 and SH3 binding sites (Carpino et al., 1997; Yamanashi and Baltimore, 1997; Di Cristofano et al., 1998; Nelms et al., 1998; Cong et al., 1999). In the present study, we identified a new subgroup of p62dok family members, dok-4 and dok-5, which associate directly with the receptor tyrosine kinase c-Ret. We show that dok-4 and dok-5 can function in c-Retmediated neurite outgrowth. In contrast to p62dok and dok-2, dok-4 and dok-5 do not bind rasGAP and play a positive role in activation of the MAP kinase pathway.
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Results |
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Discussion |
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The expression of the new dok family members overlap with c-Ret in tissues of the central and peripheral nervous system. A function of c-Ret signaling in the nervous system has been demonstrated by genetic experiments. For instance, the number of sensory neurons of dorsal root ganglia and motor neurons of the spinal cord is reduced in GDNF-deficient mice (Moore et al., 1996; Sanchez et al., 1996). Ablation of neurturin, another ligand of c-Ret, leads to loss of cells in dorsal root and trigeminal sensory ganglia (Heuckeroth et al., 1999). In addition, it has been shown that GDNF and c-Ret play an important role in development of the enteric and sympathetic nervous system and the kidney (Schuchardt et al., 1994; Moore et al., 1996; Pichel et al., 1996; Sanchez et al., 1996). However, in the latter tissues, expression of dok family members does not overlap with that of c-Ret. However, it is possible that additional dok family members that are expressed at these sites exist, or that other adapters take over dok functions. Thus, we suggest that the newly identified dok proteins, dok-4 and dok-5, can mediate c-Ret signals in a subset of neuronal tissues. Dok family members are also expressed in other tissues where c-Ret expression is weak or has not been described (Pachnis et al., 1993; Avantaggiato et al., 1994). For instance, dok-4 is strongly expressed in the vascular endothelium. We found that dok-4 can also associate with the endothelial Tie-2 receptor, suggesting that dok-4 may function as a substrate for Tie-2 in endothelia. Tie-2 has already been reported to associate with Dok-2 (Jones and Dumont, 1998); however, endothelial expression of dok-2 is not pronounced and we have not been able to detect expression in this cell type.
Other members of the dok family, dok-13, are mainly expressed in hematopoietic tissues. Several recent reports suggest an involvement of these dok proteins in lymphoid signaling: p62dok and dok-2 are strongly tyrosine phosphorylated in Bcr-Abltransformed myelogenous leukemia cells (Carpino et al., 1997; Yamanashi and Baltimore, 1997; Di Cristofano et al., 1998). Dok-2 (dok-R/FRIP) also binds directly to the IL-4 receptor (Nelms et al., 1998). It is also possible that hematopoietic dok proteins act as c-Ret substrates in lymphoid cells, since recent reports suggest an involvement of c-Ret in hematopoietic differentiation (Wasserman et al., 1995; Gattei et al., 1997, 1998, 1999; Nakayama et al., 1999). Phoshorylation of p62dok after c-Ret activation can also occur in a phosphotidyl inositol 3 kinasedependent manner (Murakami et al., 1999).
Dok family members have the typical features of multiadapter proteins such as membrane localization sequence (PH domain), receptor interaction domain (PTB domain), and several putative binding sites for downstream substrates (P-tyr and PXXP elements). The importance of direct association of particular substrates with specific receptor tyrosine kinases for activation of various signaling pathways has been demonstrated recently, e.g., IRSs are essential for insulin receptor function, FRS2 is important for fibroblast growth factor receptor and Trk signaling, and Gab-1 is an essential substrate for c-Met (Sun et al., 1991, 1995; Weidner et al., 1996; Kouhara et al., 1997; Sachs et al., 2000; Schaeper et al., 2000). c-Ret can directly associate with all dok family proteins. However, dok family members have distinct expression patterns. Differential expression of these adapter proteins thus adds another layer to the complexity and specificity of signal transduction by receptor tyrosine kinases.
Members of the hematopoietically expressed doks, dok-1 and dok-2, contain long COOH-terminal sequences with many tyrosyls and PXXP motifs adjacent to the PTB domain (e.g., 10 for dok-1). These doks have been shown to associate with rasGAP, c-Abl, and Nck (Holland et al., 1997; Yamanashi and Baltimore, 1997). Several recent reports suggest a negative role of these dok proteins in the regulation of MAP kinase (Nelms et al., 1998; Jones and Dumont, 1999; Noguchi et al., 1999; Yamanashi et al., 2000). The dok-4/5 proteins newly identified here contain short COOH-terminal tails with fewer tyrosyls and few or no PXXP motifs, and do not bind rasGAP or Nck. Moreover, when dok-4 and dok-5 are fused to c-Ret, they strongly induce MAP kinase and Elk-1 transactivation and trigger axonal outgrowth. Thus, the two subfamilies of the dok proteins, dok-13 and dok-4/5, appear to take over opposite signaling functions in cells.
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Materials and methods |
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In situ hybridization and Northern blotting
Digoxygenin-labeled RNA transcripts were synthesized with T3 or T7 RNA polymerase using a digoxygenin RNAlabeling kit (Boehringer). Whole-mount in situ hybridization was performed as described (Wilkinson, 1992). Probes used were: c-Ret, nt 11,445; dok-4, entire coding sequence plus 900 3' nucleotide sequences; dok-5, entire coding sequence plus 180 5' nucleotides; dok-2, nucleotides 469890. All probes revealed reproducible hybridization patterns when used in antisense orientation, whereas transcripts in sense orientation revealed no specific hybridization. Semithin serial sections (715 µm) were prepared from the whole-mounts embedded in Technovit 7100 (Kulzer GmbH). Mouse multiple tissue Northern blots (CLONTECH Laboratories, Inc.) were probed with 32P-labeled cDNA probes specific for dok family members prepared by the Megaprime DNA labeling kit (Amersham Pharmacia Biotech).
Construction of EGFR/c-Ret-dok chimeras and generation of PC12 transfectants
EGFR/c-Ret constructs were inserted into the SalI site of pBabe Puro retroviral expression vector (Morgenstern and Land, 1990); in EGFR/c-Ret Y1062F, tyrosine residue 1,062 was mutated to phenylalanin by PCR. Fusion constructs of EGFR/c-Ret and various dok family members were generated by insertion of dok fragments (encoding amino acids 119412, dok-2; 113325, dok-4; 116306, dok-5; and 233325, dok-4Cterm) into the XhoI site of c-ret, deleting sequences encoding the last 22 amino acids of c-Ret including Y1062. PC12 cells were infected with high titer stock of a retrovirus that contained the EGFR/c-Ret-dok constructs, and were selected for 5 d with 0.5 µg/ml puromycin. Pools of selected cultures were grown in the presence or absence of 50 ng/ml EGF for 48 h, and neurite outgrowth was quantitated by scoring cells with neurites longer than the size of two cell bodies.
MAP kinase and Elk-1 reporter assays
PC12 cells infected with retroviruses were serum-starved overnight and then treated with and without 50 ng/ml EGF for 9 h. Cells were lysed and assayed for Erk1/2 phosphorylation using the antiactive MAP kinase antibody. Neuro 2A cells were transfected with pBabe EGFR/c-Ret-dok expression plasmids, pFA2-Elk1, pFRLuc (Stratagene), and pSV40lacZ expression vectors. 2 d posttransfection, cells were stimulated with 50 ng/ml EGF for 5 h. 293 cells were transfected with c-Ret or MEN2A Ret (C634R), different amounts of dok-2 or dok-5, and reporter plasmids. Cells were lysed 2 d posttransfection by three freeze and thaw cycles, and extracts were analyzed for ß-galactosidase and luciferase activity.
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Footnotes |
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Acknowledgments |
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Submitted: 6 February 2001
Revised: 31 May 2001
Accepted: 8 June 2001
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References |
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---|
Alberti, L., M.G. Borrello, S. Ghizzoni, F. Torriti, M.G. Rizzetti, and M.A. Pierotti. 1998. Grb2 binding to the different isoforms of Ret tyrosine kinase. Oncogene. 17:10791087.[Medline]
Arighi, E., L. Alberti, F. Torriti, S. Ghizzoni, M.G. Rizzetti, G. Pelicci, B. Pasini, I. Bongarzone, C. Piutti, M.A. Pierotti, and M.G. Borrello. 1997. Identification of Shc docking site on Ret tyrosine kinase. Oncogene. 14:773782.[Medline]
Asai, N., H. Murakami, T. Iwashita, and M. Takahashi. 1996. A mutation at tyrosine 1062 in MEN2A-Ret and MEN2B-Ret impairs their transforming activity and association with shc adaptor proteins. J. Biol. Chem. 271:1764417649.
Avantaggiato, V., N.A. Dathan, M. Grieco, N. Fabien, D. Lazzaro, A. Fusco, A. Simeone, and M. Santoro. 1994. Developmental expression of the RET protooncogene. Cell Growth Differ. 5:305311.[Abstract]
Behrens, J., J.P. von Kries, M. Kuhl, L. Bruhn, D. Wedlich, R. Grosschedl, and W. Birchmeier. 1996. Functional interaction of ß-catenin with the transcription factor LEF-1. Nature. 382:638642.[Medline]
Besset, V., R.P. Scott, and C.F. Ibanez. 2000. Signaling complexes and protein-protein interactions involved in the activation of the Ras and PI3K pathways by the c-Ret receptor tyrosine kinase. J. Biol. Chem. 275:3915939166.
Bladt, F., D. Riethmacher, S. Isenmann, A. Aguzzi, and C. Birchmeier. 1995. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature. 376:768771.[Medline]
Borrello, M.G., L. Alberti, E. Arighi, I. Bongarzone, C. Battistini, A. Bardelli, B. Pasini, C. Piutti, M.G. Rizzetti, P. Mondellini, M.T. Radice, and M.A. Pierotti. 1996. The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase C. Mol. Cell. Biol. 16:21512163.[Abstract]
Carpino, N., D. Wisniewski, A. Strife, D. Marshak, R. Kobayashi, B. Stillman, and B. Clarkson. 1997. p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell. 88:197204.[Medline]
Cong, F., B. Yuan, and S.P. Goff. 1999. Characterization of a novel member of the dok family that binds and modulates Abl signaling. Mol. Cell. Biol. 19:83148325.
Di Cristofano, A., N. Carpino, N. Dunant, G. Friedland, R. Kobayashi, A. Strife, D. Wisniewski, B. Clarkson, P.P. Pandolfi, and M.D. Resh. 1998. Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins. J. Biol. Chem. 273:48274830.
Donis-Keller, H., S. Dou, D. Chi, K.M. Carlson, K. Toshima, T.C. Lairmore, J.R. Howe, J.F. Moley, P. Goodfellow, and S.A.J. Wells. 1993. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum. Mol. Genet. 2:851856.[Abstract]
Durick, K., R.Y. Wu, G.N. Gill, and S.S. Taylor. 1996. Mitogenic signaling by Ret/ptc2 requires association with enigma via a LIM domain. J. Biol. Chem. 271:1269112694.
Edery, P., S. Lyonnet, L.M. Mulligan, A. Pelet, E. Dow, L. Abel, S. Holder, F.C. Nihoul, B.A. Ponder, and A. Munnich. 1994. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature. 367:378380.[Medline]
Gattei, V., A. Celetti, A. Cerrato, M. Degan, A. De Iuliis, F.M. Rossi, G. Chiappetta, C. Consales, S. Improta, V. Zagonel, et al. 1997. Expression of the RET receptor tyrosine kinase and GDNFR- in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment. Blood. 89:29252937.
Gattei, V., M. Degan, D. Aldinucci, A. De Iuliis, F.M. Rossi, F.T. Mazzocco, M. Rupolo, V. Zagonel, and A. Pinto. 1998. Differential expression of the RET gene in human acute myeloid leukemia. Ann. Hematol. 77:207210.[Medline]
Gattei, V., M. Degan, F.M. Rossi, A. De Iuliis, F.T. Mazzocco, E. Cesa, D. Aldinucci, V. Zagonel, and A. Pinto. 1999. The RET receptor tyrosine kinase, but not its specific ligand, GDNF, is preferentially expressed by acute leukaemias of monocytic phenotype and is up-regulated upon differentiation. Br. J. Haematol. 105:225240.[Medline]
Hayashi, H., M. Ichihara, T. Iwashita, H. Murakami, Y. Shimono, K. Kawai, K. Kurokawa, Y. Murakumo, T. Imai, H. Funahashi, A. Nakao, and M. Takahashi. 2000. Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Oncogene. 19:44694475.[Medline]
Herbst, R., P.M. Carroll, J.D. Allard, J. Schilling, T. Raabe, and M.A. Simon. 1996. Daughter of sevenless is a substrate of the phosphotyrosine phosphatase Corkscrew and functions during sevenless signaling. Cell. 85:899909.[Medline]
Heuckeroth, R.O., H. Enomoto, J.R. Grider, J.P. Golden, J.A. Hanke, A. Jackman, D.C. Molliver, M.E. Bardgett, W.D. Snider, E.M.J. Johnson, and J. Milbrandt. 1999. Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron. 22:253263.[Medline]
Hofstra, R.M., R.M. Landsvater, I. Ceccherini, R.P. Stulp, T. Stelwagen, Y. Luo, B. Pasini, J.W. Hoppener, H.K. van Amstel, G. Romeo, et al. 1994. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 367:375376.[Medline]
Holland, S.J., N.W. Gale, G.D. Gish, R.A. Roth, Z. Songyang, L.C. Cantley, M. Henkemeyer, G.D. Yancopoulos, and T. Pawson. 1997. Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. EMBO J. 16:38773888.
Jones, N., and D.J. Dumont. 1998. The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R. Oncogene. 17:10971108.[Medline]
Jones, N., and D.J. Dumont. 1999. Recruitment of Dok-R to the EGF receptor through its PTB domain is required for attenuation of Erk MAP kinase activation. Curr. Biol. 9:10571060.[Medline]
Kouhara, H., Y.R. Hadari, K.T. Spivak, J. Schilling, S.D. Bar, I. Lax, and J. Schlessinger. 1997. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell. 89:693702.[Medline]
Lemay, S., D. Davidson, S. Latour, and A. Veillette. 2000. Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling. Mol. Cell. Biol. 20:27432754.
Liu, X., Q.C. Vega, R.A. Decker, A. Pandey, C.A. Worby, and J.E. Dixon. 1996. Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. J. Biol. Chem. 271:53095312.
Lorenzo, M.J., G.D. Gish, C. Houghton, T.J. Stonehouse, T. Pawson, B.A. Ponder, and D.P. Smith. 1997. RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2. Oncogene. 14:763771.[Medline]
Meakin, S.O., J.I. MacDonald, E.A. Gryz, C.J. Kubu, and J.M. Verdi. 1999. The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation. J. Biol. Chem. 274:98619870.
Molliver, D.C., D.E. Wright, M.L. Leitner, A.S. Parsadanian, K. Doster, D. Wen, Q. Yan, and W.D. Snider. 1997. IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron. 19:849861.[Medline]
Moore, M.W., R.D. Klein, I. Farinas, H. Sauer, M. Armanini, H. Phillips, L.F. Reichardt, A.M. Ryan, M.K. Carver, and A. Rosenthal. 1996. Renal and neuronal abnormalities in mice lacking GDNF. Nature. 382:7679.[Medline]
Morgenstern, J.P., and H. Land. 1990. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 18:35873596.[Abstract]
Mulligan, L.M., J.B. Kwok, C.S. Healey, M.J. Elsdon, C. Eng, E. Gardner, D.R. Love, S.E. Mole, J.K. Moore, L. Papi, et al. 1993. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 363:458460.[Medline]
Murakami, H., T. Iwashita, N. Asai, Y. Shimono, Y. Iwata, K. Kawai, and M. Takahashi. 1999. Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation. Biochem. Biophys. Res. Commun. 262:6875.[Medline]
Nakayama, S., K. Iida, T. Tsuzuki, T. Iwashita, H. Murakami, N. Asai, Y. Iwata, M. Ichihara, S. Ito, K. Kawai, M. Asai, K. Kurokawa, and M. Takahashi. 1999. Implication of expression of GDNF/Ret signalling components in differentiation of bone marrow haemopoietic cells. Br. J. Haematol. 105:5057.[Medline]
Nelms, K., A.L. Snow, L.J. Hu, and W.E. Paul. 1998. FRIP, a hematopoietic cell-specific rasGAP-interacting protein phosphorylated in response to cytokine stimulation. Immunity. 9:1324.[Medline]
Noguchi, T., T. Matozaki, K. Inagaki, M. Tsuda, K. Fukunaga, Y. Kitamura, T. Kitamura, K. Shii, Y. Yamanashi, and M. Kasuga. 1999. Tyrosine phosphorylation of p62(Dok) induced by cell adhesion and insulin: possible role in cell migration. EMBO J. 18:17481760.
O'Neill, T.J., A. Craparo, and T.A. Gustafson. 1994. Characterization of an interaction between insulin receptor substrate 1 and the insulin receptor by using the two-hybrid system. Mol. Cell. Biol. 14:64336442.[Abstract]
Pachnis, V., B. Mankoo, and F. Costantini. 1993. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 119:10051017.
Pichel, J.G., L. Shen, H.Z. Sheng, A.C. Granholm, J. Drago, A. Grinberg, E.J. Lee, S.P. Huang, M. Saarma, B.J. Hoffer, H. Sariola, and H. Westphal. 1996. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature. 382:7376.[Medline]
Raabe, T., E.J. Riesgo, X. Liu, B.S. Bausenwein, P. Deak, P. Maroy, and E. Hafen. 1996. DOS, a novel pleckstrin homology domain-containing protein required for signal transduction between sevenless and Ras1 in Drosophila. Cell. 85:911920.[Medline]
Rizzo, C., D. Califano, G.L. Colucci-D'Amato, G. De Vita, A. D'Alessio, N.A. Dathan, A. Fusco, C. Monaco, G. Santelli, G. Vecchio, M. Santoro, and V. de Franciscis. 1996. Ligand stimulation of a Ret chimeric receptor carrying the activating mutation responsible for the multiple endocrine neoplasia type 2B. J. Biol. Chem. 271:2949729501.
Romeo, G., P. Ronchetto, Y. Luo, V. Barone, M. Seri, I. Ceccherini, B. Pasini, R. Bocciardi, M. Lerone, H. Kaariainen, et al. 1994. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature. 367:377378.[Medline]
Rossel, M., A. Pasini, S. Chappuis, O. Geneste, L. Fournier, I. Schuffenecker, M. Takahashi, L.A. van Grunsven, J.L. Urdiales, B.B. Rudkin, G.M. Lenoir, and M. Billaud. 1997. Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations. Oncogene. 14:265275.[Medline]
Sachs, M., H. Brohmann, D. Zechner, T. Müller, J. Hülsken, I. Walther, U. Schaeper, C. Birchmeier, and W. Birchmeier. 2000. Essential role of Gab1 for signaling by the c-Met receptor in vivo. J. Cell Biol. 150:13751384.
Sanchez, M.P., S. Silos, I.J. Frisen, B. He, S.A. Lira, and M. Barbacid. 1996. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature. 382:7073.[Medline]
Santoro, M., W.T. Wong, P. Aroca, E. Santos, B. Matoskova, M. Grieco, A. Fusco, and P.P. di Fiore. 1994. An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway. Mol. Cell. Biol. 14:663675.[Abstract]
Schaeper, U., N.H. Gehring, K.P. Fuchs, M. Sachs, B. Kempkes, and W. Birchmeier. 2000. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. J. Cell Biol. 149:14191432.
Schuchardt, A., V. D'Agati, B.L. Larsson, F. Costantini, and V. Pachnis. 1994. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 367:380383.[Medline]
Sun, X.J., P. Rothenberg, C.R. Kahn, J.M. Backer, E. Araki, P.A. Wilden, D.A. Cahill, B.J. Goldstein, and M.F. White. 1991. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 352:7377.[Medline]
Sun, X.J., L.M. Wang, Y. Zhang, L. Yenush, J. Myers-MG, E. Glasheen, W.S. Lane, J.H. Pierce, and M.F. White. 1995. Role of IRS-2 in insulin and cytokine signalling. Nature. 377:173177.[Medline]
Suzu, S., M. Tanaka-Douzono, K. Nomaguchi, M. Yamuda, H. Hayasawa, F. Kimura, and K. Motoyoshi. 2000. p56(dok-2) as a cytokine-inducible inhibitor of cell proliferation and signal transduction. EMBO J. 19:51145122.
Tahira, T., Y. Ishizaka, F. Itoh, T. Sugimura, and M. Nagao. 1990. Characterization of ret proto-oncogene mRNAs encoding two isoforms of the protein product in a human neuroblastoma cell line. Oncogene. 5:97102.[Medline]
Takahashi, M., J. Ritz, and G.M. Cooper. 1985. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 42:581588.[Medline]
Tamir, I., J.C. Stolpa, C.D. Helgason, K. Nakamura, P. Bruhns, M. Daeron, and J.C. Cambier. 2000. The RasGAP-binding protein p62dok is a mediator of inhibitory FcgammaRIIB signals in B cells. Immunity. 12:347358.[Medline]
Treanor, J.J., L. Goodman, F. de Sauvage, D.M. Stone, K.T. Poulsen, C.D. Beck, C. Gray, M.P. Armanini, R.A. Pollock, F. Hefti, et al. 1996. Characterization of a multicomponent receptor for GDNF. Nature. 382:8083.[Medline]
Ullrich, A., and J. Schlessinger. 1990. Signal transduction by receptors with tyrosine kinase activity. Cell. 61:203212.[Medline]
van der Geer, P., T. Hunter, and R.A. Lindberg. 1994. Receptor protein-tyrosine kinases and their signal transduction pathways. Annu. Rev. Cell Biol. 10:251337.
Wasserman, R., Y.S. Li, and R.R. Hardy. 1995. Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. J. Immunol. 155:644651.[Abstract]
Weidner, K.M., S. Di Cesare, M. Sachs, V. Brinkmann, J. Behrens, and W. Birchmeier. 1996. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature. 384:173176.[Medline]
Wilkinson, D.G. 1992. In Situ Hybridization: A Practical Approach. Oxford University Press/IRL Press, NY. 224 pp.
Withers, D.J., J.S. Gutierrez, H. Towery, D.J. Burks, J.M. Ren, S. Previs, Y. Zhang, D. Bernal, S. Pons, G.I. Shulman, W.S. Bonner, and M.F. White. 1998. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 391:900904.[Medline]
Yamanashi, Y., and D. Baltimore. 1997. Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok. Cell. 88:205211.[Medline]
Yamanashi, Y., T. Tamura, T. Kanamori, H. Yamane, H. Nariuchi, T. Yamamoto, and D. Baltimore. 2000. Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling. Genes Dev. 14:1116.