1998 Fiscal Year Annual Research Report

Crkを介する癌遺伝子産生と癌抑制遺伝子産生のクロストーク

Research Project

Project/Area Number	10470064
Research Category	Grant-in-Aid for Scientific Research (B)
Research Institution	Research Institute, International Medical Center of Japan
Principal Investigator	松田道行国立国際医療センター研究所, 臨床病理研究部, 部長 (10199812)
Co-Investigator(Kenkyū-buntansha)	清川悦子国立国際衣料センター研究所, 臨床病理研究部, 研究員 (80300929)
Keywords	Crk / C3G / 癌遺伝子 / 癌抑制遺伝子
Research Abstract	本年度は、Crk癌遺伝子産物に結合するもっとも量的に多い分子であるC3Gが、Crkによりどのように活性化されるかについて検討を加えた。C3Gは癌化を抑制する低分子量GTP結合蛋白Rap1の活性化因子である。Crkを加えるとC3GのRap1活性化能が著しく亢進することを見出した。CrkにはSH2およびSH3ドメインがあるが、この両方のドメインが機能することがC3Gの活性化には必要であった。SH2ドメインの機能を欠損させた変異体に細胞膜移行シグナルを付加したところ、CrkによるC3Gの活性化能が一部復活した。SH3はCrkがC3Gに結合するために必要なので、CrkがC3Gを活性化するのはC3Gを細胞膜近傍に移行させるためであるという結論を得た。しかし、膜移行シグナルをつけたC3Gも、Crkと共発現するとさらに活性化されることを見出した。そこで、C3Gが細胞膜において何らかの修飾を受けるのではないかと考え、解析したところ、C3Gがチロシンリン酸化を受けていることを見出した。そこで、さまざまなC3Gの欠失変異体を作ったところ、C3Gのほぼ中央の領域にC3Gのチロシンリン酸化部位を見出した。さらに、C3Gのアミノ末端側を欠失したところC3GのRap1活性化能が著名に亢進した。これは、C3Gのアミノ末端側に活性を負に制御する領域があり、これがチロシンのリン酸化により解除されるというモデルを提供するものである。

Research Products

(19 results)

All Other

All Publications (19 results)

[Publications] Kiyokawa E,et al.: "Activation of Racl by a Crk SH3-binding protein,DOCK180." Genes Dev. 12. 3331-3336 (1998)
[Publications] Kawasaki H,et al.: "A novel Rap guanine nucleotide exchange factor enriched in the basal ganglia." Proc Natl Acad Sci USA. 95. 13278-13283 (1998)
[Publications] Dolfi F,et al.: "The adapter protein Crk regulates the JNK signaling pathway in response to multiple cellular stimuli." Proc Natl Acad Sci USA. 95. 15394-15399 (1998)
[Publications] Kawasaki H,et al.: "A family of cAMP-binding proteins that directly activate Rapl." Science. 282. 2275-2279 (1998)
[Publications] Kiyokawa E,et al.: "Evidence that DOCK180 up-regulates signals from the CrkII-p130Cas complex." J Biol Chem. 273. 24479-24484 (1998)
[Publications] Okada S,et al.: "Insulin regulates the dynamic balance between Ras and Rapl signaling by coordinating the assembly states of the Grb2-SOS and CrkII-C3G complexes." EMBOJ. 17. 2554-2565 (1998)
[Publications] Hashimoto Y,et al.: "Phosphorylation of CrkII adaptor protein at Tyrosine 221 by epidermal growth factor receptor." J Biol Chem. 273. 17186-17191 (1998)
[Publications] Ota S,et al.: "Constituive association of EGF receptor with the CrkII-23 mutant that inhibits transformation of NRK cells by EGF and TGF-b." Cell Signal. 10. 283-290 (1998)
[Publications] Tokunaga K,et al.: "Inhibition of HIV-1 virion entry by dominant negative Hck." J Virol. 72. 6257-6259 (1998)
[Publications] Takahashi H,et al.: "The role of topoisomerase I in hiv-1 replication." Leukemia. 11. 113-115 (1997)
[Publications] Kiyokawa E,et al.: "Role of Crk oncogene product in physiologic signaling." Crit Rev Oncog. 8. 329-342 (1997)
[Publications] Ichiba T,et al.: "Enhancement of guanine-nucleotide exchange activity of C3G for Rapl by the expression of Crk,CrkL,and Grb2." J Biol Chem. 272. 22215-22220 (1997)
[Publications] Gotoh T,et al.: "Activation of R-Ras by ras-guanine nucleotide-releasing factor." J Biol Chem. 272. 18602-18607 (1997)
[Publications] Takai S,et al.: "Chromosomal mapping of the gene encoding DOCK180,a major Crk-binding protein,to 10q26.13-q26.3 by fluorescence in situ hybridization." Genomics. 35. 403-404 (1996)
[Publications] Matsuda M.et al.: "Interaction between the amino terminal SH3 domain of CRK and its natural target proteins." J Biol Chem. 271. 14468-14472 (1996)
[Publications] Kizaka-Kondon S,et al.: "CrkII signals from epidermal growth factor receptor to Ras." Proc Natl Acad Sci USA. 93. 12177-12182 (1996)
[Publications] Ingham RJ,et al.: "B cell antigen receptor signaling induces the formation of complexes containing the Crk adapter proteins." J Biol Chem. 271. 32306-32314 (1996)
[Publications] Hasegawa H,et al: "DOCK180,a major CRK-binding protein,alters cell morphology upon translocation to the membrane." Mol Cell Biol. 16. 1770-1776 (1996)
[Publications] Annen K,et al.: "Analysis of the hepatocyte growth factor receptor in regeneration andoncogenesis of the liver." Gen Diagn pathol. 141. 179-186 (1996)

1998 Fiscal Year Annual Research Report

Crkを介する癌遺伝子産生と癌抑制遺伝子産生のクロストーク

Principal Investigator

松田 道行 国立国際医療センター研究所, 臨床病理研究部, 部長 (10199812)

Research Products

[Publications] Kiyokawa E,et al.: "Activation of Racl by a Crk SH3-binding protein,DOCK180." Genes Dev. 12. 3331-3336 (1998)

[Publications] Kawasaki H,et al.: "A novel Rap guanine nucleotide exchange factor enriched in the basal ganglia." Proc Natl Acad Sci USA. 95. 13278-13283 (1998)

[Publications] Dolfi F,et al.: "The adapter protein Crk regulates the JNK signaling pathway in response to multiple cellular stimuli." Proc Natl Acad Sci USA. 95. 15394-15399 (1998)

[Publications] Kawasaki H,et al.: "A family of cAMP-binding proteins that directly activate Rapl." Science. 282. 2275-2279 (1998)

[Publications] Kiyokawa E,et al.: "Evidence that DOCK180 up-regulates signals from the CrkII-p130Cas complex." J Biol Chem. 273. 24479-24484 (1998)

[Publications] Okada S,et al.: "Insulin regulates the dynamic balance between Ras and Rapl signaling by coordinating the assembly states of the Grb2-SOS and CrkII-C3G complexes." EMBOJ. 17. 2554-2565 (1998)

[Publications] Hashimoto Y,et al.: "Phosphorylation of CrkII adaptor protein at Tyrosine 221 by epidermal growth factor receptor." J Biol Chem. 273. 17186-17191 (1998)

[Publications] Ota S,et al.: "Constituive association of EGF receptor with the CrkII-23 mutant that inhibits transformation of NRK cells by EGF and TGF-b." Cell Signal. 10. 283-290 (1998)

[Publications] Tokunaga K,et al.: "Inhibition of HIV-1 virion entry by dominant negative Hck." J Virol. 72. 6257-6259 (1998)

[Publications] Takahashi H,et al.: "The role of topoisomerase I in hiv-1 replication." Leukemia. 11. 113-115 (1997)

[Publications] Kiyokawa E,et al.: "Role of Crk oncogene product in physiologic signaling." Crit Rev Oncog. 8. 329-342 (1997)

[Publications] Ichiba T,et al.: "Enhancement of guanine-nucleotide exchange activity of C3G for Rapl by the expression of Crk,CrkL,and Grb2." J Biol Chem. 272. 22215-22220 (1997)

[Publications] Gotoh T,et al.: "Activation of R-Ras by ras-guanine nucleotide-releasing factor." J Biol Chem. 272. 18602-18607 (1997)

[Publications] Takai S,et al.: "Chromosomal mapping of the gene encoding DOCK180,a major Crk-binding protein,to 10q26.13-q26.3 by fluorescence in situ hybridization." Genomics. 35. 403-404 (1996)

[Publications] Matsuda M.et al.: "Interaction between the amino terminal SH3 domain of CRK and its natural target proteins." J Biol Chem. 271. 14468-14472 (1996)

[Publications] Kizaka-Kondon S,et al.: "CrkII signals from epidermal growth factor receptor to Ras." Proc Natl Acad Sci USA. 93. 12177-12182 (1996)

[Publications] Ingham RJ,et al.: "B cell antigen receptor signaling induces the formation of complexes containing the Crk adapter proteins." J Biol Chem. 271. 32306-32314 (1996)

[Publications] Hasegawa H,et al: "DOCK180,a major CRK-binding protein,alters cell morphology upon translocation to the membrane." Mol Cell Biol. 16. 1770-1776 (1996)

[Publications] Annen K,et al.: "Analysis of the hepatocyte growth factor receptor in regeneration andoncogenesis of the liver." Gen Diagn pathol. 141. 179-186 (1996)

松田道行国立国際医療センター研究所, 臨床病理研究部, 部長 (10199812)