1996 Fiscal Year Annual Research Report

細胞接着と細胞増殖におけるC-キナーゼの役割

Research Project

Project/Area Number	06283222
Research Institution	Yokohama City University
Principal Investigator	大野茂男横浜市立大学, 医学部, 教授 (10142027)
Co-Investigator(Kenkyū-buntansha)	鈴木厚横浜市立大学, 医学部, 助手 (00264606) 水野恵子横浜市立大学, 医学部, 助手 (90221803)
Keywords	プロテインキナーゼC / S6キナーゼ / ストレス応答 / NFkB / メタロプロティナーゼ
Research Abstract	PKCは細胞内シグナル経路の調節因子として極めて重要であることが様々な実験から推測されてきたが、未だにその具体的な作用点は不明である。本研究では、従来の研究で集積したPKCに関する独自の材料を用いて、PKCの具体的な作用点を解明することを目的とし、以下の二つの方向からのアプローチを行い、以下の結果を得た。 1)PI3キナーゼ経路の代表的な下流因子、p70S6キナーゼの活性化機構を解析し、これにaPKCλが関わっていることを明らかにした。 2)nPKCδ結合蛋白質として細胞膜貫通型のタンパク質を同定した。これはメタロプロテイナーゼ/ディスインテグリンファミリーの仲間であり、PKCδはこの細胞質ドメインに特異的に結合する。細胞接着とシグナル伝達経路との接点となっている事が予測され、きわめて興味深い。 3)aPKCλ結合タンパク質として、PDZドメインを有する新規タンパク質を見いだした。これは線虫の卵の不等分裂に関わる遺伝子のほ乳類版であった。 4)Rafを介したMAPキナーゼの活性化過程において、Ras以外に必要な因子として、PKCδを同定した。 5)ストレス応答MAPキナーゼ(SAPK/JNK)経路の上流キナーゼとして、MUK、MST/MLK2を同定し、これらがSEKを介してSAPK/JNKを活性化することを示した。SAPK/JNKの上流には、MEKKに加えてMUK/MLKファミリーが存在する。 6)SAPK/JNK上流因子の一つであるMEKKがTNFαによるNFkBの活性化経路に関わることを見出した。

Research Products
(19 results)

All Other

All Publications (19 results)

[Publications] Fukumoto, S.: "Protein kinase C delta isoform inhibits the proliferation of vascular smooth muscle cells through suppressiong G1 cyclins expression." J.Biol.Chem.272(in press.).
[Publications] Hirai, S.: "MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of JNK/SAPK." J.Biol.Chem.272(in press.).
[Publications] Izumi, Y.: "A protein kinase C delta-binding protein SRBC whose expression is induced by serum starvation." J.Biol.Chem.272(in press.).
[Publications] Osada, S.: "A domain containing the Cdc42/Rac interactive binding (CRIB) region of p65PAK inhibits transcriptional activation and cell transformation mediated by the Ras-Rac pathway." FEBS Letter. (in press.).
[Publications] Osada, S.: "YSK1, a novel mammalian protein kinase structurally related to Ste20 and SPS1, but not involved in the known MAPK pathways." Oncogene. 14(in press.).
[Publications] Ohno, S.: "The distinct biological potential of PKC isotypes." in Protein Kinase C. 75-93 (1996)
[Publications] Zappelli, F.: "The inhibition of differentiation caused by TGFbeta in fetal myoblasts is dependent upon selective expression of PKCtheta : a possible molecular basis for myoblast diversification during limb histogenesis." Dev.Biol.180. 156-164 (1996)
[Publications] Takayanagi, I.: "Dominant negative effects of the trucated p110 subunit of phosphatidylinositol-3 kinase." Biochem. Mol.Biol.Int.39. 721-728 (1996)
[Publications] Chalfant, C.E.: "A carboxy-terminal deletion mutant of PKCbeta II inhibits insulin-stimulated 2-deoxyglucose uptake in rat L6 skeletal muscle cells." Molecular Endocrinology. 10. 1273-1281 (1996)
[Publications] Chalfant, C.E.: "A carboxy-terminal deletion mutant of PKCbeta II inhibits insulin-stimulated 2-deoxyglucose uptake in rat L6 skeletal muscle cells." Molecular Endocrinology. (in press.).
[Publications] Ueda, Y.: "Protein kinase Cδ activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf." J.Biol.Chem.271. 23512-23519 (1996)
[Publications] Rana, A.: "The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1." J.Biol.Chem.271. 19025-19028 (1996)
[Publications] Sauma. S.: "Protein kinase Cβ1 and protein kinase Cβ2 activate p57 mitogen-activated protein kinase and block differentiation in colon carcinoma cells." Cell Growth Differentiation. 7. 587-594 (1996)
[Publications] Nakaigawa, N.: "Differential effects of overexpression of PKCα and PKCδ/ε on cellular E2F activity at late G1 phase." Biochem. Biophys. Res.Commun.222. 95-100 (1996)
[Publications] Hirano, M.: "MEK kinase is involved in TNFα-mediated activation of NFκB and degradation of IκBα." J.Biol.Chem.271. 13234-13238 (1996)
[Publications] Ueda, E.: "The η isoform of protein kinase C mediates transcriptional activation of the human transglutaminase 1 gene." J.Biol.Chem.271. 9790-9794 (1996)
[Publications] Akimoto, K.: "EGF and PDGF receptors activate atypical PKCλ through phosphatidylinositol 3-kinase." EMBO J.15. 788-798 (1996)
[Publications] Hirai, S.: "Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK." Oncogene. 12. 641-650 (1996)
[Publications] Moriya, S.: "PDGF activates protein kinase Cε through redundant and independent signaling pathways involving phosphpholipase Cγ or phosphatidylinositol 3-kinase." Proc Natl.Acad.Sci.U.S.A.93. 151-155 (1996)

1996 Fiscal Year Annual Research Report

細胞接着と細胞増殖におけるC-キナーゼの役割

Principal Investigator

大野 茂男 横浜市立大学, 医学部, 教授 (10142027)

Research Products

[Publications] Fukumoto, S.: "Protein kinase C delta isoform inhibits the proliferation of vascular smooth muscle cells through suppressiong G1 cyclins expression." J.Biol.Chem.272(in press.).

[Publications] Hirai, S.: "MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of JNK/SAPK." J.Biol.Chem.272(in press.).

[Publications] Izumi, Y.: "A protein kinase C delta-binding protein SRBC whose expression is induced by serum starvation." J.Biol.Chem.272(in press.).

[Publications] Osada, S.: "A domain containing the Cdc42/Rac interactive binding (CRIB) region of p65PAK inhibits transcriptional activation and cell transformation mediated by the Ras-Rac pathway." FEBS Letter. (in press.).

[Publications] Osada, S.: "YSK1, a novel mammalian protein kinase structurally related to Ste20 and SPS1, but not involved in the known MAPK pathways." Oncogene. 14(in press.).

[Publications] Ohno, S.: "The distinct biological potential of PKC isotypes." in Protein Kinase C. 75-93 (1996)

[Publications] Zappelli, F.: "The inhibition of differentiation caused by TGFbeta in fetal myoblasts is dependent upon selective expression of PKCtheta : a possible molecular basis for myoblast diversification during limb histogenesis." Dev.Biol.180. 156-164 (1996)

[Publications] Takayanagi, I.: "Dominant negative effects of the trucated p110 subunit of phosphatidylinositol-3 kinase." Biochem. Mol.Biol.Int.39. 721-728 (1996)

[Publications] Chalfant, C.E.: "A carboxy-terminal deletion mutant of PKCbeta II inhibits insulin-stimulated 2-deoxyglucose uptake in rat L6 skeletal muscle cells." Molecular Endocrinology. 10. 1273-1281 (1996)

[Publications] Chalfant, C.E.: "A carboxy-terminal deletion mutant of PKCbeta II inhibits insulin-stimulated 2-deoxyglucose uptake in rat L6 skeletal muscle cells." Molecular Endocrinology. (in press.).

[Publications] Ueda, Y.: "Protein kinase Cδ activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf." J.Biol.Chem.271. 23512-23519 (1996)

[Publications] Rana, A.: "The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1." J.Biol.Chem.271. 19025-19028 (1996)

[Publications] Sauma. S.: "Protein kinase Cβ1 and protein kinase Cβ2 activate p57 mitogen-activated protein kinase and block differentiation in colon carcinoma cells." Cell Growth Differentiation. 7. 587-594 (1996)

[Publications] Nakaigawa, N.: "Differential effects of overexpression of PKCα and PKCδ/ε on cellular E2F activity at late G1 phase." Biochem. Biophys. Res.Commun.222. 95-100 (1996)

[Publications] Hirano, M.: "MEK kinase is involved in TNFα-mediated activation of NFκB and degradation of IκBα." J.Biol.Chem.271. 13234-13238 (1996)

[Publications] Ueda, E.: "The η isoform of protein kinase C mediates transcriptional activation of the human transglutaminase 1 gene." J.Biol.Chem.271. 9790-9794 (1996)

[Publications] Akimoto, K.: "EGF and PDGF receptors activate atypical PKCλ through phosphatidylinositol 3-kinase." EMBO J.15. 788-798 (1996)

[Publications] Hirai, S.: "Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK." Oncogene. 12. 641-650 (1996)

[Publications] Moriya, S.: "PDGF activates protein kinase Cε through redundant and independent signaling pathways involving phosphpholipase Cγ or phosphatidylinositol 3-kinase." Proc Natl.Acad.Sci.U.S.A.93. 151-155 (1996)

大野茂男横浜市立大学, 医学部, 教授 (10142027)