A PP2A Regulatory Subunit Regulates C-elegans Insulin/IGF-1 Signaling by Modulating AKT-1 Phosphorylation

被引：134

作者：

Padmanabhan, Srivatsan ^{[1
]}

Mukhopadhyay, Arnab ^{[1
]}

Narasimhan, Sri Devi ^{[1
]}

Tesz, Gregory ^{[2
]}

Czech, Michael P. ^{[2
]}

Tissenbaum, Heidi A. ^{[1
,2
]}

机构：

[1] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA

[2] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA

来源：

CELL | 2009年 / 136卷 / 05期

关键词：

PROTEIN-KINASE-B; FORKHEAD TRANSCRIPTION FACTOR; TUMOR-SUPPRESSOR GENE; AGE-1; PI3; KINASE; CAENORHABDITIS-ELEGANS; LIFE-SPAN; STRESS RESISTANCE; DAUER FORMATION; CELL-PROLIFERATION; LARVAL DEVELOPMENT;

D O I：

10.1016/j.cell.2009.01.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The C. elegans insulin/IGF-1 signaling (IIS) cascade plays a central role in regulating life span, dauer, metabolism, and stress. The major regulatory control of IIS is through phosphorylation of its components by serine/threonine-specific protein kinases. An RNAi screen for serine/threonine protein phosphatases that counterbalance the effect of the kinases in the IIS pathway identified pptr-1, a B56 regulatory subunit of the PP2A holoenzyme. Modulation of pptr-1 affects IIS pathway-associated phenotypes including life span, dauer, stress resistance, and fat storage. We show that PPTR-1 functions by regulating worm AKT-1 phosphorylation at Thr 350. With striking conservation, mammalian B56 beta regulates Akt phosphorylation at Thr 308 in 3T3-L1 adipocytes. In C. elegans, this ultimately leads to changes in subcellular localization and transcriptional activity of the forkhead transcription factor DAF-16. This study reveals a conserved role for the B56 regulatory subunit in regulating insulin signaling through AKT dephosphorylation, thereby having widespread implications in cancer and diabetes research.

引用

页码：939 / 951

页数：13

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