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Mechanism of the Expression of Various Phenotypes in Multiple Endocrine Neoplasia Type 2

Research Project

Project/Area Number 10671112
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionNagoya University

Principal Investigator

IMAI Tsuneo  School of Medicine, Nagoya University, Assistant Professor, 医学部, 講師 (80252245)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Masahide  School of Medicine, Nagoya University, Professor, 医学部, 教授 (40183446)
FUNAHASHI Hiroomi  School of Medicine, Nagoya University, Assistant Professor, 医学部, 講師 (50135357)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywordsret proto-oncogene / MEN2A / MEN2B / Shc / PI3-K / Gab1 / GDNF / MAPK / ret proto-oncogene / PI3-k / tyrasine kinase / MEN 2A / MEN 2B / PTB / SH2 / tyrosine kinase
Research Abstract

Germ line mutations in ret proto-oncogene result in human hereditary diseases including MEN2A and MEN2B.MEN2A mutations induced disulfide-linked dimerization of the RET whereas MEN2B mutations appear to activate RET without dimerization. Tyrosine 1062 in RET represents a binding site for Shc adaptor proteins and is crucial for both RAS/ MAPK and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, Shc bound to Gab1 and Grb2 adaptor proteins as well as RET, and Shc and Gab1 were highly phosphorylated on tyrosine. The complex formation consisting of Shc, Gab1 and Grb2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine, Tyrosine-phosphorylated Gab1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas Shc-Grb2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through Shc bound to tyrosine 1062 in RET.Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-kappaB in GDNF-treated cells, respectively.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Hayashi H, et al.: "Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell-lined derived neurotrophic factor"Oncogene. 19. 4469-4475 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawai K, et al.: "Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation"Cancer Research. 60. 5254-5260 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwashita T, et al.: "A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations"Biochem Biocphys Res Commun. 268. 804-808 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishiguro Y, et al.: "The role of amino acids surrounding tyrosine 1062 in Ret in specific binding of the Shc phosphotyrosine binding domain"Endocrinology. 140. 3992-3998 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Murakami H, et al.: "Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by Ret with the MEN2B mutation"Biochem Biophys Res Commun. 262. 68-75 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T, et al.: "A case controlled study of laparoscopic compared to open lateral adrenalectomy"American J Surgery. 178. 50-53 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 今井常夫: "内分泌外科の要点と盲点(Knack & Pitfallsシリーズ)IV副腎.2.副腎腫瘍の診断・手術適応決定のKnack & Pitfalls.3)褐色細胞腫"文光堂. 248 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hayashi H, Ichihara M, Iwashita T, Murakami H, Shimono Y, Kawai K, Kurokawa K, Murakumo Y, Imai T, Funahashi H, Nakao A, Takahashi M.: "Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell-lined derived neurotrophic factor."Oncogene. 19. 4469-4475 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawai K, Iwashita T, Murakami H, Hiraiwa N, Yoshiki A, Kusakabe M, Ono K, Iida K, Nakayama A, Takahashi M.: "Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation."Cancer Res. 60. 5254-5260 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A, Futami H, Qiao S, Ichihara M, Takahashi M.: "A two-hit model for development of multiple endocrine neoplasia type 2B RET mutations."Biochem Biocphys Res Commun. 268. 804-808 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ishiguro Y, Iwashita T, Murakami H, Asai N, Iida K, Goto H, Hayakawa T, Takahashi M.: "The role of amino acids surrounding tyrosine 1062 in Ret in specific binding of the Shc phosphotyrosine binding domain."Endocrinology. 140. 3992-3998 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Murakami H, Iwashita T, Asai N, Shimono Y, Iwata Y, Kawai K, Takahashi M.: "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. 68-75 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T, Kikumori T, Ohiwa M, Matsuura N, Mase T, Funahashi H.: "A case controlled study of laparoscopic compared to open lateral adrenalectomy."American J Surgery. 178. 50-53 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Imai T, Tanaka Y, Kikumori T, Ohiwa M, Matsuura N, Mase T, Funahashi H.: "Surgical management of preclinical medullary thyroid carcinoma in MEN2A."Thyroidology Clinical and Experimental. 10. 143-147 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hayashi H et al.: "Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell-lined derived neurotrophic factor"Oncogene. 19. 4469-4475 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kawai K et al.: "Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation"Cancer Research. 60. 5254-5260 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Iwashita T et al.: "A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations"Biochem Biocphys Res Commun. 268. 804-808 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ishiguro Y et al.: "The role of amino acids surrounding tyrosine 1062 in Ret in specific binding of the Shc phosphotyrosine binding domain"Endocrinology. 140. 3992-3998 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Murakami H et al.: "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. 68-75 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Imai T et al.: "A case controlled study of laparoscopic compared to open lateral adrenalectomy"American J Surgery. 178. 50-53 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] 今井常夫: "内分泌外科の要点と盲点(Knack & Pitfallsシリーズ)IV 副腎.2.副腎腫瘍の診断・手術適応決定のKnack & Pitfalls.3)褐色細胞腫"文光堂. 248 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] IMAI T,et al: "Surgical management of preclinical medullary thyroid carcinoma in MEN2A"Thyroidology Clinical and Experimental. 10. 143-147 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] IMAI T,et al: "Virilizing adrenocortical adenoma"Surgery. 125. 396-402 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] IMAI T,et al: "Laparoscopic partial adrenalectomy"Surgical Endoscopy. 13. 343-345 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] IMAI T,et al: "A case control study of laparoscopic compared to open lateral adrenck"American J.Surgery. 178. 50-53 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 今井常夫: "内分泌外科の要点と盲点 褐色細胞腫"文光堂 幕内雅敏監修 小原孝男 編集. 248 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Imai T.et al.: "Surgical management of preclinical medullary thyroid carcinoma in MEN2A" Thyroidology Clinical and Experimental. 10. 143-147 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Lmi T.et al.: "Laparostopic partial adrenalectomy" Surgical Endoscopy. 13 (in press). (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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