Akt (PKB) is the cellular homolog of the oncoprotein of the AKT8 retrovirus (Bellacosa et al. 1991). Members of the mammalian Akt family, Akt1, 2 and 3, are activated by PI3K in response to tropic factors (e.g., insulin and other mitogens); other routes of activation are suspected (Datta et al. 1999; Plas and Thompson 2005; Sarbassov et al. 2005b). In Fig. 1, the binding of insulin to the insulin receptor (IR) is used as an example of an Akt activator. IR activation results in tyrosine phosphorylation of insulin receptor substrates (IRSs), this allows binding of the p85 regulatory subunit of PI3K to IRSs. Consequently, the PI3K catalytic subunit (p110) is activated and phosphorylates phosphatidylinositol (PI)-4,5-bisphosphate (PIP2) to PI-3,4,5-triphosphate (PIP3) on the plasma membrane. Both Akt and phosphoinositide-dependent protein kinase-1 (PDK1) bind PIP3, allowing PDK1 to be positioned to phosphorylate (activate) Akt on threonine 308 (T308).
Activated Akt affects multiple cellular targets that increase metabolism, growth and proliferation while suppressing apoptosis (Summers et al. 1998; Ueki et al. 1998; Cass et al. 1999; Datta et al. 1999; Hill et al. 1999; Plas and Thompson 2005). All of these are beneficial to HCMV lytic growth. Thus, it is not surprising that Akt is activated during HCMV infection (Johnson et al. 2001; Yu and Alwine 2002; Kudchodkar et al. 2006). One of the downstream effects of activated Akt is the activation of mTOR kinase (also known as RAFT1 or FRAP) in mTOR complex 1 (mTORC1, Fig. 1, described in detail in Sect. 3 below). Activation of mTORC1 is critical for the maintenance of cap-dependent translation.
The link between Akt and mTORC1 is (1) the tuberous sclerosis complex (TSC; reviewed in Luo et al. 2005), made up of TSC1 [hamartin] and TSC2 [tuberin] and (2) Rheb-GTP, a member of the Ras superfamily which binds the N-terminal lobe of the mTOR kinases catalytic domain, allowing mTOR activation (Astrinidis and Henske 2005; Long et al. 2005a, 2005b). Regulation of Rheb-GTP levels is mediated by the GTPase-activating function of the TSC, which stimulates the intrinsic GTPase activity of Rheb, converting it from Rheb-GTP to Rheb-GDP, the inactive form that cannot activate mTORC1. Thus Akt's phosphorylation of the TSC inactivates it, allowing Rheb-GTP levels to remain high in order to activate mTORC1.
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