rictor-mTOR复合物对Akt/PKB的磷酸化及调控

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.

作者信息

Sarbassov D D, Guertin David A, Ali Siraj M, Sabatini David M

机构信息

Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA.

出版信息

Science. 2005 Feb 18;307(5712):1098-101. doi: 10.1126/science.1106148.

DOI:10.1126/science.1106148

PMID:15718470

Abstract

Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on Ser473 in vitro and facilitated Thr308 phosphorylation by PDK1. Rictor-mTOR may serve as a drug target in tumors that have lost the expression of PTEN, a tumor suppressor that opposes Akt/PKB activation.

摘要

Akt/蛋白激酶B（PKB）的失调与癌症和糖尿病的发病机制有关。Akt/PKB的激活需要磷酸肌醇依赖性激酶1（PDK1）使激活环中的苏氨酸308磷酸化，以及一种未知激酶使羧基末端疏水基序中的丝氨酸473磷酸化。我们发现，在果蝇和人类细胞中，雷帕霉素靶蛋白（TOR）激酶及其相关蛋白rictor是丝氨酸473磷酸化所必需的，并且rictor或哺乳动物TOR（mTOR）表达的降低会抑制Akt/PKB效应器。rictor-mTOR复合物在体外直接使Akt/PKB的丝氨酸473磷酸化，并促进PDK1对苏氨酸308的磷酸化。rictor-mTOR可能成为在已失去肿瘤抑制因子PTEN（一种抑制Akt/PKB激活的蛋白）表达的肿瘤中的药物靶点。