肿瘤抑制因子PTEN/MMAC1可使脂质第二信使磷脂酰肌醇-3,4,5-三磷酸去磷酸化。

The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.

作者信息

Maehama T, Dixon J E

机构信息

Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0606, USA.

出版信息

J Biol Chem. 1998 May 29;273(22):13375-8. doi: 10.1074/jbc.273.22.13375.

DOI:10.1074/jbc.273.22.13375

PMID:9593664

Abstract

Phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) is a key molecule involved in cell growth signaling. We demonstrated that overexpression of PTEN, a putative tumor suppressor, reduced insulin-induced PtdIns(3,4,5)P3 production in human 293 cells without effecting insulin-induced phosphoinositide 3-kinase activation. Further, transfection of the catalytically inactive mutant of PTEN (C124S) caused PtdIns(3,4,5)P3 accumulation in the absence of insulin stimulation. Purified recombinant PTEN catalyzed dephosphorylation of PtdIns(3,4,5)P3, specifically at position 3 on the inositol ring. PTEN also exhibited 3-phosphatase activity toward inositol 1,3,4,5-tetrakisphosphate. Our results raise the possibility that PTEN acts in vivo as a phosphoinositide 3-phosphatase by regulating PtdIns(3,4,5)P3 levels. As expected, the C124S mutant of PTEN was incapable of catalyzing dephosphorylation of PtdIns(3,4,5)P3 consistent with the mechanism observed in protein-tyrosine phosphatase-catalyzed reactions.

摘要

磷脂酰肌醇-3,4,5-三磷酸（PtdIns(3,4,5)P3）是参与细胞生长信号传导的关键分子。我们证明，一种假定的肿瘤抑制因子PTEN的过表达可降低胰岛素诱导的人293细胞中PtdIns(3,4,5)P3的产生，而不影响胰岛素诱导的磷酸肌醇3-激酶激活。此外，转染PTEN的催化失活突变体（C124S）会在无胰岛素刺激的情况下导致PtdIns(3,4,5)P3积累。纯化的重组PTEN催化PtdIns(3,4,5)P3的去磷酸化，具体是在肌醇环的3位。PTEN对肌醇-1,3,4,5-四磷酸也表现出3-磷酸酶活性。我们的结果提出了一种可能性，即PTEN在体内通过调节PtdIns(3,4,5)P3水平作为一种磷酸肌醇3-磷酸酶发挥作用。正如预期的那样，PTEN的C124S突变体无法催化PtdIns(3,4,5)P3的去磷酸化，这与在蛋白酪氨酸磷酸酶催化反应中观察到的机制一致。