Cytokine receptor γc chain mediated signal transduction and analysis of immunodeficiency by dysfunction of the γc chain

• Project/Area Number: 10470084
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Tohoku University
• Principal Investigator: TAKESHITA Toshokazu Tohoku University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (60212023)
• Co-Investigator(Kenkyū-buntansha): ISHII Naoto Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (60291267)
• Project Period (FY): 1998 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥12,800,000 (Direct Cost: ¥12,800,000); Fiscal Year 1999: ¥6,100,000 (Direct Cost: ¥6,100,000); Fiscal Year 1998: ¥6,700,000 (Direct Cost: ¥6,700,000)
• Keywords: IL-2 receptor / the γc chain / Jak3 / SCID / STAM / IL-2 / STAM2

Research Abstract

The interleukin 2 receptor γ chain (IL-2Rγ ), which we previously cloned, is known to be a causative gene for human X-linked severe combined immunodeficiency (X-SCID). X-SCID is a disease that occurs in as many as 50% of patients with primary SCID, and is characterized with profound defect of T and NK cells and impairment of B cell differentiation. The IL-2Rγ is shared among the receptors for several cytokines, and called the common γ(γc) chain. The cytoplasmic domain of the γc chain is associated with Jak3 tyrosine kinase, of which mutantions also cause an autosomal recessive SCID, Jak3-SCID. These observations suggest that the γc/Jak3 signaling pathway is indispensable for development of T, NK and B cells. We thus hypothesized that molecules involved in the γc/Jak3 signaling pathway may include causative gene products for SCID. In this context, we have identified STAM1, which is associated with Jak3 and Jak2, and involved in signaling for cell proliferation and c-myc induction mediated by IL-2 and GM-CSF. STAM1 knockout mice were born and developed normally, but their body weights decreased gradually after 5 weeks of age, and were below 60-70% of those of normal mice. 90% of the mice died before 16 weeks of age. Until 4 weeks of age, STAM1 knockout mice were normal clinically, but histopathologically they showed an abnormality in the CA3 region of the hippocampus. On the other hand, we molecularly cloned a STAM1 homologous molecule named STAM2, and revealed that STAM2 has similar in vitro functions to STAM1, suggesting that STAM1 may be compensated by STAM2 in the STAM1 knockout mice. We have also developed STAM2 knockout mice, which show normal growth and no abnormal features so far. We are now attempting to establish double KO mice for STAM1 and STAM2 to examine their possible functional relationship.

Research Products

• [Journal Article] Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family. (1999)
  • Author(s): Abe, H., et al.
  • Journal Title: Gene 227 Pages: 71-77
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular cloning of a glycosylphosphatidylinositol-anchored molecule CDw108. (1999)
  • Author(s): Yamada, A., et al.
  • Journal Title: J.Immunol. 162 Pages: 4094-4100
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Grf40,a novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76and LAT. (1999)
  • Author(s): Asada, H., et al.
  • Journal Title: J.Exp.Med. 189 Pages: 1383-1390
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Possible involvement of a novel STAM-associated molecule "AMSH" in intracellular signal transduction mediate by cytokines. (1999)
  • Author(s): Tanaka, N., et al.
  • Journal Title: J.Biol.Chem. 274 Pages: 19129-19135
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular cloning, chromosome mapping and characterization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family. (1999)
  • Author(s): Abe, H., Takeshita, T., Nagata, K., Arita, T., Endo, Y., Fujita, T., Takayama, H., Kubo, M., Sugamura, K.
  • Journal Title: Gene Vol.227 Pages: 71-77
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular cloning of a glycosylphosphatidylinositol-anchored molecule CDw108. (1999)
  • Author(s): Yamada, A., Kubo, K., Takeshita, T., Harashima, N., Kawano, K., Mine, T., Sagawa, K., Sugamura, K., Itoh, K.
  • Journal Title: J.Immunol. Vol.162 Pages: 4094-4100
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Grf40, a novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT. (1999)
  • Author(s): Asada, H., Ishii, N., Sasaki, Y., Endo, K., Kasai, H., Tanaka, N., Takeshita, T., Tsuchiya, S., Konno, T., Sugamura, K.
  • Journal Title: J.Exp.Med. Vol.189 Pages: 1383-1390
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Possible involvement of a novel STAM-associated molecule "AMSH" in intracellular signal transduction mediate by cytokines. (1999)
  • Author(s): Tanaka, N., Kaneko, K., Asao, H., Kasai, H., Endo, Y., Fujita, T., Takeshita, T., Sugamura K.
  • Journal Title: J.Biol.Chem. Vol.274 Pages: 19129-19135
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prolongation of allograft survival by administration of mAb specific for the three subunits of IL-2 receptor. (1998)
  • Author(s): Yasuda, K., et al.
  • Journal Title: Int.Immunol. 10 Pages: 561-567
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prolongation of allograft survival by administration of mAb specific for the three subunis of IL-2 receptor. (1998)
  • Author(s): Yasuda, K., Nemoto, T., Ohashi, Y., Satomi, S., Mutara, K., Ishii, N., Takeshita, T., Sugamura, K.
  • Journal Title: Int.Immunol. Vol.10 Pages: 561-567
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Tanaka N. et al.: "Possible involvement of a novel STAM-associated molecule "AMSH" in intracellular signal transduction mediated by cytokines"J. Biol. Chem.. 274. 19129-19135 (1999)
• [Publications] Asada H. et al.: "Grf40, A novel grb2 family member, is involved ih T cell signaling through interaction with SLP-76 and LAT"J. Exp. Med.. 189. 1383-1390 (1999)
• [Publications] Abe H. et al.: "Molecular cloning, chromosome mapping and charactrization of the mouse CRTH2 gene, a putative member of the leukocyte chemoattractant receptor family"Gene. 227. 71-77 (1999)
• [Publications] Yasuda,K.: "Prolongation of allograft survival by administration of mAb specific for the three subunits of IL-2 receptor." Int.Immunol.10. 561-567 (1998)