Wednesday 24 November 2004
Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids implicated in the regulation of cell growth, proliferation, survival, differentiation, and cytoskeletal changes. One of the best characterized targets of PI3K lipid products are AKTs (AKT1 and AKT2) (protein kinases B or PKBs).
The serine/threonine protein kinase AKT1 (also known as PKB, protein kinase B) is thought to be a key mediator of signal transduction processes. The identification of AKT1 substrates and the role AKT1 phosphorylation plays in regulating these molecules have been a major focus of research in recent years. AKT1 plays a key role in cancer progression by stimulating cell proliferation and inhibiting apoptosis and is also probably a key mediator of insulin signalling.
In quiescent cells, AKT1 resides in the cytosol in a low-activity conformation. Upon cellular stimulation, AKT1 is activated through recruitment to cellular membranes by PI3K lipids and by phosphorylation by 3-prime phosphoinositide-dependent kinase-1 (PDPK1) (MIM.605213).
PTEN suppresses phosphoinositol-3-kinase (PI3K) signaling, thereby down-regulating downstream mediators, including the oncogenic serine-threonine kinase AKT1, which in turn regulates the mTOR (mammalian target of rapamycin) growth pathway.
A mosaic activating mutation in AKT1 associated with the Proteus syndrome. (#21793738#)
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005 Dec;4(12):988-1004. PMID: #16341064#
Whiteman EL, Cho H, Birnbaum MJ. Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab. 2002 Dec;13(10):444-51. PMID: #12431841#
A mosaic activating mutation in AKT1 associated with the Proteus syndrome. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O’Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. N Engl J Med. 2011 Aug 18;365(7):611-9. PMID: #21793738#