Abstract
The Akt family of serine/threonine protein kinases are key regulators of multiple aspects of cell behaviour, including proliferation, survival, metabolism, and tumorigenesis. Growth-factor-activated Akt signalling promotes progression through normal, unperturbed cell cycles by acting on diverse downstream factors involved in controlling the G1/S and G2/M transitions. Remarkably, several recent studies have also implicated Akt in modulating DNA damage responses and genome stability. High Akt activity can suppress ATR/Chk1 signalling and homologous recombination repair (HRR) via direct phosphorylation of Chk1 or TopBP1 or, indirectly, by inhibiting recruitment of double-strand break (DSB) resection factors, such as RPA, Brca1, and Rad51, to sites of damage. Loss of checkpoint and/or HRR proficiency is therefore a potential cause of genomic instability in tumor cells with high Akt. Conversely, Akt is activated by DNA double-strand breaks (DSBs) in a DNA-PK- or ATM/ATR-dependent manner and in some circumstances can contribute to radioresistance by stimulating DNA repair by nonhomologous end joining (NHEJ). Akt therefore modifies both the response to and repair of genotoxic damage in complex ways that are likely to have important consequences for the therapy of tumors with deregulation of the PI3K-Akt-PTEN pathway.
Highlights
Akt Family KinasesAs one of the most versatile kinase families, Akt ( known as PKB) serine-threonine kinases function as critical regulators of cell survival, proliferation, metabolism, and migration
The Akt family of serine/threonine protein kinases are key regulators of multiple aspects of cell behaviour, including proliferation, survival, metabolism, and tumorigenesis
Akt is activated by DNA double-strand breaks (DSBs) in a DNA-PK- or ATM/ATR-dependent manner and in some circumstances can contribute to radioresistance by stimulating DNA repair by nonhomologous end joining (NHEJ)
Summary
As one of the most versatile kinase families, Akt ( known as PKB) serine-threonine kinases function as critical regulators of cell survival, proliferation, metabolism, and migration. Findings from Akt isoform-specific knockout mice suggest that Akt family kinases are likely to have distinct biological functions in vivo. PIP3 functions to activate downstream signaling components by recruiting proteins containing PH domains to the plasma membrane, such as Akt and PDK1 kinases [14,15,16,17]. CAMP elevating agents have been shown to activate Akt through PKA [22, 23], whilst Ca2+/calmodulin-dependent kinase can directly phosphorylate and activate Akt in vitro [24, 25] Several nonkinase interactors such as Hsp, Hsp, Tcl, Geb, and Ft1 have been described to positively regulate Akt catalytic activity [13]. Codeletion of PHLPP1 and PTEN is strongly associated with metastatic prostate cancer and tightly correlated to deletion of p53 and PHLPP1, suggesting the role of PHLPP as a prostate tumor suppressor [37]
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