Fig. 1.

Model of differential activation of PI3K/Akt signaling by growth factors and HCMV infection. (A) Growth factors binding to their cognate receptors activate canonical PI3K signaling, leading to activation of Akt through phosphorylation at T308 and S473 by PDK1 and mTORC2, respectively. (B) During lytic infection, a biphasic activation of PI3K/Akt occurs with an early transient burst of activation mediated by PDGFR, EGFR, and/or integrin engagement followed by a sustained secondary activation mediated by viral proteins IE72 and IE86. Both T308 and S473 appear to be phosphorylated during lytic infection. (C) The atypical activation of PI3K/Akt during quiescent infection of monocytes is initiated by HCMV binding to EGFR and integrins. The coordinated action of PI3K’s catalytic isoform p110β, as opposed to the predominant p110δ isoform found in monocytes, and SHIP-1 leads to preferential phosphorylation of Akt at S473 by a yet to be identified mechanism. While not much is known about the PI3K activity during latency, EGFR is believed to be activated during HCMV entry in CD34+ cells and PI3K has been observed to be rapidly upregulated during early latent infection.