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Balancing Akt with S6K

Brendan D. Manning

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115

Correspondence to Brendan D. Manning: bmanning{at}hsph.harvard.edu

Abstract

Proper regulation of the phosphoinositide 3-kinase–Akt pathway is critical for the prevention of both insulin resistance and tumorigenesis. Many recent studies have characterized a negative feedback loop in which components of one downstream branch of this pathway, composed of the mammalian target of rapamycin and ribosomal S6 kinase, block further activation of the pathway through inhibition of insulin receptor substrate function. These findings form a novel basis for improved understanding of the pathophysiology of metabolic diseases (e.g., diabetes and obesity), tumor syndromes (e.g., tuberous sclerosis complex and Peutz-Jegher's syndrome), and human cancers.

Abbreviations used in this paper: 4E-BP1, eIF4E-binding protein 1; eIF4E, eukaryotic initiation factor 4E; FFA, free fatty acid; IGF, insulin-like growth factor; IRS, insulin receptor substrate; JNK, c-Jun NH₂-terminal kinase; MEF, mouse embryonic fibroblast; PI3K, phosphoinositide 3-kinase; RTK, receptor tyrosine kinase; S6K, ribosomal S6 kinase; TNF-, tumor necrosis factor ; TOR, target of rapamycin; TSC, tuberous sclerosis complex.

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