tailieunhanh - Báo cáo khoa học: Constitutively active a subunits of Gq/11 and G12/13 families inhibit activation of the pro-survival Akt signaling cascade

Accumulating evidence indicates that G protein signaling plays an active role in the regulation of cell survival. Our previous study demonstrated the regulatory effects of Gi⁄ o proteins in nerve growth factor-induced activa-tion of pro-survival Akt kinase. In the present study we explored the role of various members of the Gs,Gq⁄ 11 and G12⁄ 13 subfamilies in the regula-tion of Akt in cultured mammalian cells. | iFEBS Journal Constitutively active a subunits of Gq 11 and G12 13 families inhibit activation of the pro-survival Akt signaling cascade Eddy H. T. Wu Becky H. L. Tam and Yung H. Wong Department of Biochemistry the Molecular Neuroscience Center and the Biotechnology Research Institute Hong Kong University of Science and Technology Clear Water Bay Kowloon Hong Kong China Keywords Akt cell survival G protein growth factor tuberin Correspondence Y. H. Wong Department of Biochemistry Hong Kong University of Science and Technology Clear Water Bay Kowloon Hong Kong China Fax 852 2358 1552 Tel 852 2358 7328 E-mail boyung@ Received 14 November 2005 revised 23 February 2006 accepted 22 March 2006 doi Accumulating evidence indicates that G protein signaling plays an active role in the regulation of cell survival. Our previous study demonstrated the regulatory effects of Gi o proteins in nerve growth factor-induced activation of pro-survival Akt kinase. In the present study we explored the role of various members of the Gs Gq 11 and G12 13 subfamilies in the regulation of Akt in cultured mammalian cells. In human embryonic kidney 293 cells transiently expressing constitutively active mutants of Ga11 Ga14 Ga16 Ga12 or Ga13 Ga11QL Ga14QL Ga16QL Ga12QL and Ga13QL respectively basal phosphorylation of Akt was attenuated as revealed by western blotting analysis using a phosphospecific anti-Akt immunoglobulin. In contrast basal Akt phosphorylation was unaffected by the overexpression of a constitutively active Gas mutant GasQL . Additional experiments showed that Ga11QL Ga14QL Ga16QL Ga12QL and Ga13QL but not GasQL attenuated phosphorylation of the Akt-regulated translation regulator tuberin. Moreover they were able to inhibit the epidermal growth factor-induced Akt activation and tuberin phosphorylation. The inhibitory mechanism of Gq family members was independent of phospholipase Cb activation and calcium signaling because Ga11QL Ga14QL and