PRAS40: target or modulator of mTORC1 signalling and insulin action?
Alterations in signalling via protein kinase B (PKB/Akt) and the mammalian target of rapamycin (mTOR) frequently occur in type 2 diabetes and various human malignancies. Proline-rich Akt substrate of 40-kDa (PRAS40) has a regulatory function at the intersection of these pathways. The interaction of PRAS40 with the mTOR complex 1 (mTORC1) inhibits the activity of mTORC1. Phosphorylation of PRAS40 by PKB/Akt and mTORC1 disrupts the binding between mTORC1 and PRAS40, and relieves the inhibitory constraint of PRAS40 on mTORC1 activity. This review summarizes the signalling pathways regulating PRAS40 phosphorylation, as well as the dual function of PRAS40 as substrate and inhibitor of mTORC1 in the physiological situation, and under pathological conditions, such as insulin resistance and cancer.
Nascimento
Emmani B M
EB
Department of Molecular Cell Biology, Section Signal Transduction and Ageing, Leiden University Medical Centre, Leiden, The Netherlands.
Ouwens
D Margriet
DM
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*
C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases