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1 RTK G GPCR α PI - vasculogenesis angiogenesis phosphatidylinositol PI - PI K PI PI K PI K Vps PI K PI K α PI K PI K-C α PI K PI K PI K A pα β γ δ PI P PI P PI K PI K-C α, -C β, -C γ Waterfield PI K_ D C α C β PI PIP C α C β C α C β C γ Vps Vacuolar protein sorting- hvps PIP PI K PIP PI P PI P PI P PI P PH pleckstrin homology Akt PH PI K Akt G PI K Ras Rho Rho Rac cdc Arf GEF GTPase GAP B pα pβ KO EE

2 ７７６生化学第８５巻第９号図１ PI３キナーゼファミリーの分類 A とホスファチジルイノシトール PtdIns 情報伝達経路 B みにれびゆう

3 I-A PI K pδ KO Vanhaesebroeck TLR pδ I-B pγ KO pγ pα KO pα A VEGF-A Akt Rho pα in vivo VEGF-Akt Rho PI K PtdInsP FYVE EEA early endosome antigen- C α PI K C α C α in vitro C β KO C β KO in vitro LPA C β RNA RNAi α PI K-C α C α C α KO C α E E E A C α KO C α KO CKO SM α-cre; C α flox flox Nkx - - Cre; C α flox flox CKO C α ΔEC Tie -Cre; C α flox flox CKO B C α C α ΔEC C α C α-cko Cdh PAC -CreER T ; C α flox flox C α iδec C α iδec C α P P C α iδec C α PI K C α in vivo C α iδec C α iδec Lewis LLC B B -BL C α iδec C α iδec C α iδec

4 PI K-C α

5 NG C α RNAi C α HUVEC VEGF-A pα VEGF-A PI K pβ C β Vps C α HUVEC VEGF-A VEGF Akt MAP ERK PAK NO enos VEGF PI K pα C α G RhoA RhoA Rho MYPT VEGF-A - S P RacFGF Rap C α C α G C α C α C α PIP mrfp xfyve PIP PIP C α FYVE pα Vps C α PIP C α TGN PIP GFP VE C VE C α-rhoa RhoA FRET Raichu-RhoA RhoA VEGF-A RhoA RhoA EEA C α RhoA D PIP RhoA C α RhoA VEGF VEGFR VEGF-A VEGFR FYVE C α C α VEGF-A VEGFR VEGFR C α Dynasore VEGF-A RhoA VE- C α VEGFR RhoA VE GPCR S P S P S P C α S P G Gi Rac VEGF RhoA S P RacFRET EEA C α RacS P S P C α C α PI K VEGF-A S P PI K-C α

6 C α PI K C α PIP E C α C α PI K pα β PI K Akt VE- APPL SARA Vps PI K PIP Vps PI K C α PI K Adams, R.H. & Alitalo, K.Nat. Rev. Mol. Cell Biol.,,. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M., & Bilanges, B.Nat. Rev. Mol. Cell Biol.,,. Yoshioka, K., Yoshida, K., Cui, H., Wakayama, T., Takuwa, N., Okamoto, Y., Du, W., Qi, X., Asanuma, K., Sugihara, K., Aki, S., Miyazawa, H., Biswas, K., Nagakura, C., Ueno, M., Iseki, S., Schwartz, R.J., Okamoto, H., Sasaki, T., Matsui, O., Asano, M., Adams, R.H., Takakura, N., & Takuwa, Y. Nat. Med.,,. Biswas, K., Yoshioka, K., Asanuma, K., Okamoto, Y., Takuwa, N., Sasaki, T., & Takuwa, Y.J. Biol. Chem.,,. Bi, L., Okabe, I., Bernard, D.J., Wynshaw-Boris, A., & Nussbaum, R.L.J. Biol. Chem.,,. Bi, L., Okabe, I., Bernard, D.J., & Nussbaum, R.L. Mamm. Genom.,,. Aksoy, E., Taboubi, S., Torres, D., Delbauve, S., Hachani, A., Whitehead, M.A., Pearce, W.P., Berenjeno-Martin, I., Nock, G., Filloux, A., Beyaert, R., Flamand, V., & Vanhaesebroeck, B.Nat. Immunol.,,. Crackower, M.A., Oudit, G.Y., Kozieradzki, I., Sarao, R., Sun, H., Sasaki, T., Hirsch, E., Suzuki, A., Shioi, T., Irie-Sasaki, J., Sah, R., Cheng, H.Y., Rybin, V.O., Lembo, G., Fratta, L., Oliveira-dos-Santos, A.J., Benovic, J.L., Kahn, C.R., Izumo, S., Steinberg, S.F., Wymann, M.P., Backx, P.H., & Penninger, J. M.Cell,,. Graupera, M., Guillermet-Guibert, J., Foukas, L.C., Phng, L.K., Cain, R.J., Salpekar, A., Pearce, W., Meek, S., Millan, J., Cutillas, P.R., Smith, A.J., Ridley, A.J., Ruhrberg, C., Gerhardt, H., & Vanhaesebroeck, B.Nature,,. Domin, J., Gaidarov, I., Smith, M.E., Keen, J.H., & Waterfield, M.D.J. Boil. Chem.,,. Di Paolo, G. & De Camilli, P.Nature,,. Harada, K., Truong, A.N., Cai, T., & Khavari, P.A. Mol. Cell Biol.,,. Domin, J., Harper, L., Aubyn, D., Wheeler, M., Florey, O., Haskard, D., Yuan, M., & Zicha, D.J. Cell Physiol.,,. Ryu, Y., Takuwa, N., Sugimoto, N., Sakurada, S., Usui, S., Okamoto, H., Matsui, O., & Takuwa, Y.Circ. Res.,,. Zoncu, R., Perera, R.M., Balkin, D.M., Pirruccello, M., Toomre, D., & De Camilli, P.Cell,,. Kang, J.S., Liu, C., & Derynck, R.Trends Cell Biol.,,. Gould, G.W. & Lippincott-Schwartz, J.Nat. Rev. Mol. Cell Biol.,,. Physiological roles of Class II PI kinase-c α in endothelial cells Kazuaki Yoshioka, Noriko Takuwa, Yasuo Okamoto and Yoh Takuwa Department of Physiology, Kanazawa University School of Medicine, Takaramachi, Kanazawa, Ishikawa, Japan, Department of Health and Medical Sciences, Ishikawa Prefectural Nursing University