A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation.
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 B56beta 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.
Padmanabhan
Srivatsan
S
University of Massachusetts Medical School, Worcester, 01605, USA.
Mukhopadhyay
Arnab
A
Narasimhan
Sri Devi
SD
Tesz
Gregory
G
Czech
Michael P
MP
Tissenbaum
Heidi A
HA
D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity; D010744:Phosphoric Monoester Hydrolases / Q000032:analysis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
D029742:Caenorhabditis elegans Proteins; C064359:DAF-1 protein, C elegans; D007328:Insulin; D011956:Receptors, Cell Surface; C539316:pptr-1 protein, C elegans; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; C494915:akt-1 protein, C elegans; D010744:Phosphoric Monoester Hydrolases