Intracellular Signaling by the ret Tyrosine Kinase

Part of the Medical Intelligence Unit book series (MIU.LANDES)


Signaling by receptors with tyrosine kinase activity (RTK) plays an important role in the control of such cellular processes as cell growth, differentiation and motility. The binding of growth factors to RTKs promotes the activation of their intrinsic tyrosine kinase function and their interaction with a repertoire of intracellular molecules that elicit the appropriate biological response.1 In some cases “gain of function” mutations lead to a constitutive activation of the receptor and, as a consequence, to a chronic stimulation of its intracellular signaling pathway.2 Indeed, many members of the RTK gene superfamily were initially isolated as oncogenes that arose from mutations deregulating their kinase activity. Ret, a member of the RTK family, was first isolated as a transforming gene created by a recombination with the rfp gene during transfection of a T cell lymphoma DNA.


PC12 Cell Papillary Thyroid Carcinoma Medullary Thyroid Carcinoma Multiple Endocrine Neoplasia Type Familial Medullary Thyroid Carcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kazlauskas A. Receptor tyrosine kinases and their targets. Current Opinion in Genetics and Development 1994; 4: 5–14.PubMedCrossRefGoogle Scholar
  2. 2.
    Bishop JM. Molecular themes in oncogenesis. Cell 1991; 64: 235–48.PubMedCrossRefGoogle Scholar
  3. 3.
    Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985; 42: 581–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Takahashi M, Buma T, Iwamoto Y et al. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 1988; 3: 571–8.PubMedGoogle Scholar
  5. 5.
    Iwamoto T, Taniguchi M, Asai N et al. cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily. Oncogene 1993; 8: 107–91.Google Scholar
  6. 6.
    Schuchardt A, Srinivas S, Pachnis V et al. Isolation and characterization of a chicken homolog of the c-ret proto-oncogene. Oncogene 1995; 10: 641–9.PubMedGoogle Scholar
  7. 7.
    Sugaya R, Ishimaru S, Hosoya T et al. A Drosophila homolog of human proto-oncogene ret transiently expressed in embryonic neu-ronal precursor cells including neuroblasts and CNS cells. Mechanisms of Development 1994; 45: 139–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Pachnis V, Mankoo B, Costantini F. Expression of the c-RET proto-oncogene during mouse embryogenesis. Development 1993; 119: 1005–17.PubMedGoogle Scholar
  9. 9.
    Avantaggiato V, Dathan NA, Grieco M. et al. Developmental expression of the RET protooncogene. Cell Growth and Diff 1994; 5: 305–11.Google Scholar
  10. 10.
    Tsuzuki T, Takahashi M, Asai N et al. Spatial and temporal expression of the ret proto-oncogene product in embryonic, infant and adult rat tissues. Oncogene 1995; 10: 191–8.PubMedGoogle Scholar
  11. 11.
    Fabien N, Paulin C, Santoro M et al. Expression of the RET proto-oncogene in normal human C-cells and adrenal medulla. Int J Onc 1994; 4: 623–6.Google Scholar
  12. 12.
    Fabien N, Paulin C, Santoro M et al. The RET proto-oncogene is expressed in predominantly epithelial human thymomas. Int J Onc 1994; 5: 489–93.Google Scholar
  13. 13.
    Schuchardt A, D’Agati V, Larsson-Blomberg L et al. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor ret. Nature 1994; 367: 380–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Romeo G, Ronchetto P, Luo Y et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994; 367: 377–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Edery P, Lyonnet S, Mulligan LM et al. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994; 367: 378–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Santoro M, Rosati R, Grieco M et al. The ret proto-oncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene 1990; 5: 1595–8.PubMedGoogle Scholar
  17. 17.
    Ikeda I, Ishizaka Y, Tahira T et al. Specific expression of the ret proto-oncogene in human neuroblastoma cell lines. Oncogene 1990; 5: 1291–6.PubMedGoogle Scholar
  18. 18.
    Santoro M, Carlomagno F, Romano A et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 1995; 267: 381–3.PubMedCrossRefGoogle Scholar
  19. 19.
    Asai N, Iwashita T, Matsuyama M et al. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 1995; 15: 1613–9.PubMedGoogle Scholar
  20. 20.
    Fusco A, Grieco M, Santoro M et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 1987; 328: 170–2.PubMedCrossRefGoogle Scholar
  21. 21.
    Bongarzone I, Pierotti MA, Monzini N et al. High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene 1989; 4: 1457–62.PubMedGoogle Scholar
  22. 22.
    Grieco M, Santoro M, Berlingieri MT et al. PTC is a novel rearranged form of the ret proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990; 60: 557–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Santoro M, Carlomagno F, Hay ID et al. RET oncogene activation in human thyroid neoplasms is restricted to the papillary carcinoma subtype. J Clin Invest 1992; 89: 1517–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Grieco M, Cerrato A, Santoro M et al. Cloning and characterization of H4 (D10S170), a gene involved in RET rearrangements in vivo. Oncogene 1994; 9: 2531–5.PubMedGoogle Scholar
  25. 25.
    Pierotti MA, Santoro M, Jenkins RB et al. Characterization of a chromosome 10q inversion juxtaposing RET and H4 genes and creating the oncogenic sequence PTC. Proc Natl Acad Sci USA 1992; 89: 1616–20.PubMedCrossRefGoogle Scholar
  26. 26.
    Bongarzone I, Monzini N, Borrello MG et al. Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine-kinase and the regulatory subunit RI alpha of cyclic AMP protein kinase A. Mol Cell Biol 1993; 13: 358–66.PubMedGoogle Scholar
  27. 27.
    Santoro M, Dathan NA, Berlingieri MT et al. Molecular characterization of RET/PTC3: a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene 1994; 9: 509–16.PubMedGoogle Scholar
  28. 28.
    Bongarzone I, Butti MG, Coronelli S et al. Frequent activation of the ret proto-oncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res 1994; 54: 2979–85.PubMedGoogle Scholar
  29. 29.
    Lanzi C, Borrello MG, Bongarzone I et al. Identification of the product of two oncogenic rearranged forms of the RET proto-oncogene in papillary thyroid carcinomas. Oncogene 1992; 7: 2189–94.PubMedGoogle Scholar
  30. 30.
    Santoro M, Sabino N, Ishizaka Y et al. Involvement of RET oncogene in human tumors: specificity of RET activation to thyroid tumors. Br J Cancer 1993; 68: 460–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Iwamoto T, Takahashi M, Ito M et al. Oncogenicity of the ret transforming gene in MMTV/ret transgenic mice. Oncogene 1990; 5: 533–42.Google Scholar
  32. 32.
    Iwamoto T, Takahashi M, Ito M et al. Aberrant melanogenesis and melanocytic tumor development in transgenic mice that carry a metallothionein/ret fusion gene. EMBO J 1991; 10: 3167–75.PubMedGoogle Scholar
  33. 33.
    Fusco A, Berlingieri MT, Di Fiore PP et al. One and two-step transformation of rat thyroid epithelial cells by retroviral oncogenes. Mol Cell Biol 1987; 7: 3365–70.PubMedGoogle Scholar
  34. 34.
    Santoro M, Melillo RM, Berlingieri MT et al. The TRK and RET tyrosine-kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. Cell Growth and Diff 1993; 4: 77–84.Google Scholar
  35. 35.
    Schlessinger J. SH2/SH3 signaling proteins. Current Biology 1994; 4: 25–30.Google Scholar
  36. 36.
    Santoro M, Wong WT, Aroca P et al. An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway. Mol Cell Biol 1994; 14: 663–75.PubMedGoogle Scholar
  37. 37.
    Majerus PW, Ross TS, Cunningham TW et al. Recent insights in phosphatidylinositol signaling. Cell 1990; 63: 459–65.PubMedCrossRefGoogle Scholar
  38. 38.
    Escobedo JA, Kaplan DR, Kavanaugh WM et al. A phosphatidylinositol-3 kinase binds to platelet-derived growth factor receptors through a specific receptor sequence containing phosphotyrosine. Mol Cell Biol 1991; 11: 1125–32.PubMedGoogle Scholar
  39. 39.
    Hu P, Margolis B. Skolnik R et al. Interaction of phosphatidylinositol-3 kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mol Cell Biol 1992; 12: 981–90.PubMedGoogle Scholar
  40. 40.
    Whitman M, Kaplan DR, Schaffhausen B et al. Association of phosphatidylinositol kinase activity with polyoma middle T competent for transformation. Nature 1985; 315: 239–42.PubMedCrossRefGoogle Scholar
  41. 41.
    Songyang Z, Shoelson SE, Chauduri G et al. SH2 domains recognize specific phosphopeptide sequences. Cell 1993; 72: 767–78.PubMedCrossRefGoogle Scholar
  42. 42.
    McCormick F. Activators and effectors of ras p21 proteins. Current Opinion in Genetics and Development 1994; 4: 71–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Grieco D, Dathan NA, Santoro M et al Activated RET oncogene products induce maturation of Xenopus oocytes. Oncogene 1995; 11: 113–7.PubMedGoogle Scholar
  44. 44.
    Pelicci G, Lanfrancone L, Grignani F et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 1992; 70: 93–104.PubMedCrossRefGoogle Scholar
  45. 45.
    Borrello MG, Pelicci G, Arighi E et al. The oncogenic versions of the RET and TRK tyrosine kinases bind she and Grb2 adaptor proteins. Oncogene 1994; 9: 1661–8.PubMedGoogle Scholar
  46. 46.
    Serth J, Weber W, French M et al. Binding of the H-ras p21 GTPase activating protein by the activated epidermal growth factor receptor leads to inhibition of the p21 GTPase activity in vitro. Biochemistry 1992; 31: 6361–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Nobes C, Hall A. Regulation and function of the Rho subfamily of small GTPases. Current opinion in genetics and development 1994; 4: 77–81.PubMedCrossRefGoogle Scholar
  48. 48.
    Herskowitz I. MAP kinase pathways in yeast: for mating and more. Cell 1995; 80: 187–97.PubMedCrossRefGoogle Scholar
  49. 49.
    Lange-Carter CA, Johnson GL. Ras-dependent growth factor regulation of MEK kinase in PC12 cells. Science 1994; 265: 1458–61.PubMedCrossRefGoogle Scholar
  50. 50.
    Roberts TM. A signal chain of events. Nature 1992; 360: 534–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Marshall CJ. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Current Biology 1994; 4: 82–9.CrossRefGoogle Scholar
  52. 52.
    D’Arcangelo G, Halegoua S. A branched signaling pathway for nerve growth factor is revealed by Src-, Ras-, and raf-mediated gene inductions. Mol Cell Biol 1993; 13: 3146–55.PubMedGoogle Scholar
  53. 53.
    Porras A, Muszynski, Rapp UR et al. Dissociation between activa-tion of Raf-1 kinase and the 42-kDa mitogen-activated protein kinase/90-kDA S6 kinase (MAPK/RSK) cascade in the insulin/Ras pathway of adipocytic differentiation of 3T3 L1 cells. J Biol Chem 1994; 269: 12741–8.PubMedGoogle Scholar
  54. 54.
    Qureshi SA, Alexandropoulos K, Rim M et al. Evidence that Ha-Ras mediated two distinguishable intracellular signals activated by v-Src. J Biol Chem 1992; 267: 17635–9.PubMedGoogle Scholar
  55. 55.
    Polakis P, McCormick F. Interactions between p21 ras proteins and their GTPase activating proteins. Cancer Sury 1992; 12: 25–42.Google Scholar
  56. 56.
    Rodriguez-Viciana P, Warne PH, Dhand R et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994; 370: 527–32.PubMedCrossRefGoogle Scholar
  57. 57.
    Berra E, Diaz-Meco MT, Dominguez I et al. Protein kinase isoform is critical for mitogenic signal transduction. Cell 1993; 74: 555–63.PubMedCrossRefGoogle Scholar
  58. 58.
    Cai H, Erhardt P, Troppmair J et al. Hydrolysis of phosphatidylcholine couples Ras to activation of Raf protein kinase during mitogenic signal transduction. Mol Cell Biol 1993; 13: 7645–51.PubMedGoogle Scholar
  59. 59.
    Hunter T. Cooperation between oncogenes. Cell 1991; 64: 249–70.PubMedCrossRefGoogle Scholar
  60. 60.
    Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992; 13: 596–611.PubMedGoogle Scholar
  61. 61.
    Al-Alawi N, Rose DW, Buckmaster C et al. Thyrotropin-induced mitogenesis is ras dependent but appears to bypass the raf dependent cytoplasmic kinase cascade. Mol Cell Biol 1995; 15: 1162–8.PubMedGoogle Scholar
  62. 62.
    Hofstra RMW, Landsvater RM, Ceccherini I et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367: 375–76.PubMedCrossRefGoogle Scholar
  63. 63.
    Songyang Z, Carraway III KL, Eck MJ et al. Catalytic specificity of protein-tyrosine kinases is critical for selective signaling. Nature 1995; 373: 536–40.PubMedCrossRefGoogle Scholar
  64. 64.
    van der Geet P, Hunter T, Lindberg RA. Receptor protein-tyrosine kinases and their signal transduction pathways. Ann Rev Cell Biol 1994; 10: 251–337.CrossRefGoogle Scholar
  65. 65.
    Ben-Baruch N, Yarden Y. Neu differentiation factors: a family of alternatively spliced neuronal and mesenchymal factors. Proc Soc Exp Biol Med 1994; 206: 221–7.PubMedGoogle Scholar
  66. 66.
    Gherardi E, Sharpe M, Lane K et al. Hepatocyte growth factor/ scatter factor (HGF/SF), the c-met receptor and the behavior of epithelial cells. Symp Soc Exp Biol 1993; 47: 163–81.PubMedGoogle Scholar
  67. 67.
    Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995; 80: 179–85.PubMedCrossRefGoogle Scholar
  68. 68.
    Hill CS, Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 1995; 80: 199–211.PubMedCrossRefGoogle Scholar
  69. 69.
    Greenberger JS, Sakakeeny MA, Humphries RK et al. Demonstration of permanent factor-dependent multipotential (erythroid/neu-trophil/basophil) hematopoietic progenitor cell lines. Proc Natl Acad Sci USA 1983; 80: 2931–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Pierce JH, Ruggiero M, Fleming TP et al. Signal transduction through the EGF receptor transfected in IL-3 dependent hematopoietic cells. Science 1988; 239: 628–31.PubMedCrossRefGoogle Scholar
  71. 71.
    Romano A, Wong WT, Santoro M et al. The high transforming potency of erbB-2 and ret is associated with phosphorylation of paxillin and a 23 kDa protein. Oncogene 1994; 9: 2923–33.PubMedGoogle Scholar
  72. 72.
    Turner CE. Paxillin is a major phosphotyrosine-containing protein during embryonic development. J Cell Biol 1991; 115:201–7.Google Scholar
  73. 73.
    Turner CE, Miller JT. Primary sequence of paxillin contains putative SH2 and SH3 domain binding motifs and multiple LIM domains: identification of a vinculin and pp125Fak-binding region. J Cell Sci 1994; 107: 1583–91.PubMedGoogle Scholar
  74. 74.
    Fazioli F, Minichiello L, Matoska P et al. Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J 1993; 12: 3799–808.PubMedGoogle Scholar
  75. 75.
    Wong WT, Carlomagno F, Druck T et al. Evolutionary conservation of the EPS8 gene and its mapping to human chromosome 12q23-q24. Oncogene 1994; 9: 3057–61.PubMedGoogle Scholar
  76. 76.
    Fazioli F, Minichiello L, Matoskova B et al. eps15, a novel tyrosine kinase substrate exhibits transforming activity. Mol Cell Biol 1993; 13: 5814–28.PubMedGoogle Scholar
  77. 77.
    Wong WT, Kraus MH, Carlomagno F et al. The human eps 15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31-p32. Oncogene 1994; 9: 1591–7.PubMedGoogle Scholar
  78. 78.
    Bretscher A. Rapid phosphorylation and reorganization of ezrin and spectrin accompany morphological changes induces in A-431 cells by epidermal growth factor. J Cell Biol 1989; 108: 921–30.PubMedCrossRefGoogle Scholar
  79. 79.
    Greene LA, Tischler AS. Establishment of a noradrenergic clonal line of rat adrenal phaeochromocytoma cells that respond to nerve growth factor. Proc Natl Acad Sci USA 1976; 76: 2424–8.CrossRefGoogle Scholar
  80. 80.
    Ohmichi M, Pang L, Ribon V et al. Divergence of signaling pathways for insulin in PC12 pheochromocytoma cells. Endocrinology 1993; 133: 46–56.PubMedCrossRefGoogle Scholar
  81. 81.
    Califano D, Monaco C, De Vita G et al. Activated RET/PTC oncogene elicits immediate early and delayed response genes in PC12 cells. Oncogene 1995; 11: 107–12.PubMedGoogle Scholar
  82. 82.
    Pawson T, Hunter T. Signal transduction and growth control in normal and cancer cells. Current Opinion in Genetics and Development 1994; 4: 1–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

There are no affiliations available

Personalised recommendations