Role of PRAS40 in Akt and mTOR signaling in health and disease

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and...

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Bibliographic Details
Published in:American journal of physiology: endocrinology and metabolism 2012-06, Vol.302 (12), p.E1453-E1460
Main Authors: Wiza, Claudia, Nascimento, Emmani B M, Ouwens, D Margriet
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - biosynthesis
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - physiology
Animals
Conserved Sequence
Diabetes
Disease
Gene Expression Regulation - physiology
Health
Humans
Kinases
Mammals
Medicin och hälsovetenskap
Metabolism
Phosphorylation
Protein Binding
Proto-Oncogene Proteins c-akt - physiology
Signal Transduction - genetics
Signal Transduction - physiology
Substrates
TOR Serine-Threonine Kinases - physiology
Transcription Factors - genetics
Transcription Factors - physiology
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Summary:The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.
ISSN:0193-1849
1522-1555
1522-1555
DOI:10.1152/ajpendo.00660.2011