Akt: a double-edged sword in cell proliferation and genome stability

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.

Figure 1

Role of Akt in normal cell cycle progression. Activated Akt kinase modulates the function of numerous proteins involved in cell cycle progression at the G1/S and G2/M transitions, either by direct phosphorylation of the target proteins themselves, or indirectly, by regulating protein expression levels. Please see text for additional explanation.

Figure 2

Crosstalk between Akt and DNA damage signalling pathways. Akt can be activated in response to DNA damage through the action of the PI3 kinase-like kinases (PIKKs) ATM, ATR, and DNA-PK. Conversely, active Akt can promote DNA repair via NHEJ and inhibit checkpoint signalling and repair via recombination through multiple mechanisms and targets. Please see text for additional explanation.

Figure 3

Molecular mechanisms and targets for Akt-mediated genomic instability. Akt can inhibit DNA repair, recombination, and checkpoint signalling by phosphorylating key regulatory proteins such as Chk1, TopBP1, Brca1, and RPS3 at specific sites. Please see text for additional explanation.