AKT-independent PI3-K signaling in cancer - emerging role for SGK3

Abstract

The phosphoinositide 3-kinase (PI3-K) signaling pathway plays an important role in a wide variety of fundamental cellular processes, largely mediated via protein kinase B/v-akt murine thymoma viral oncogene homolog (PKB/AKT) signaling. Given the crucial role of PI3-K/AKT signaling in regulating processes such as cell growth, proliferation, and survival, it is not surprising that components of this pathway are frequently dysregulated in cancer, making the AKT kinase family members important therapeutic targets. The large number of clinical trials currently evaluating PI3-K pathway inhibitors as a therapeutic strategy further emphasizes this. The serum- and glucocorticoid-inducible protein kinase (SGK) family is made up of three isoforms, SGK1, 2, and 3, that are PI3-K-dependent, serine/threonine kinases, with similar substrate specificity to AKT. Consequently, the SGK family also regulates similar cell processes to the AKT kinases, including cell proliferation and survival. Importantly, there is emerging evidence demonstrating that SGK3 plays a critical role in AKT-independent oncogenic signaling. This review will focus on the role of SGK3 as a key effector of AKT-independent PI3-K oncogenic signaling.

Keywords: AKT; PI3-kinase; SGK3; cancer; mTOR.

Figure 1

PI3-K signaling. Notes: Activation of class I PI3-K via RTK phosphorylates and activates downstream target PDK1, in turn phosphorylating AKT kinases at the threonine site. Full activation of AKT requires phosphorylation at the serine residue by the mTORC2. Activated AKT mediates a plethora of effects through phosphorylation of a number of downstream targets including TSC2 and PRAS40. Additional factors such as HIF1α, LKB, c-MYC and the RAS signaling pathway are also able to link into PI3-K signaling at multiple levels and contribute to protein synthesis and cell growth signaling. At the endosome, class III PI3-K hVps34 is able to mediate amino acid signaling to mTORC1. Abbreviations: AKT, v-akt murine thymoma viral oncogene homolog; AMPK, 5′ AMP-activated protein kinase; HIF1α, hypoxia-inducible factor 1 alpha; hVps34, class III PI3-K human vacuolar sorting protein 34; LKB, liver kinase B1; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; PDK1, 3-phosphoinositide-dependent kinase 1; PI3-K, phosphoinositide 3-kinase; PRAS40, proline-rich AKT substrate of 40 kDa; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinases; TSC1, tuberous sclerosis factor 1; TSC2, tuberous sclerosis factor 2; Rheb, Ras homolog enriched in brain; REDD1, DNA damage inducible transcript 4; eIF4E, eukaryotic translation initiation factor 4E; 4EB-P1, eukaryotic translation initiation factor 4E binding protein 1; rpS6, ribosomal protein S6.

Figure 2

The SGK3 protein domain structure. Notes: SGK3 variants containing a PX domain in the N-terminal region between amino acids 12–120, allowing SGK3 to bind to PI(3)P, and localize to the early endosomes. SGK3 has two key regulatory sites, consisting of Serine 486 in the C-terminal hydrophobic motif and Threonine 320 in the activation loop of the catalytic domain, both of which require phosphorylation for complete activation. Abbreviations: PI(3)P, phosphatidylinositol 3-phosphate; PX, phox homology; SGK3, serum and glucocorticoid inducible kinase 3; T, threonine; S, serine.

Figure 3

PI3-K signaling via SGK3 and AKT. Notes: Activation of PI3-K by growth factor receptors leads to phosphorylation of PDK1, subsequently leading to phosphorylation and activation of AKT and SGK3. Following activation these kinases have shown to regulate TSC2 and PRAS40, leading to activation of mTORC1, an important node in signaling to protein synthesis and cell growth. In addition, AKT and SGK3 regulate FOXO3a, BAD, and GSK3β, allowing regulation of cell survival. SGK3 is also able to regulate AIP4 and FLI-I, affecting cell migration and cell survival, respectively. Abbreviations: AIP4, atrophin-1 interacting protein 4; AKT, v-akt murine thymoma viral oncogene homolog; BAD, Bcl-2 associated death promoter; FLI-I, flightless-I; FOXO3a, forkhead transcription factor 3a; GSK3β, glycogen synthase kinase β; hVps34, class III PI3-K human vacuolar sorting protein 34; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; mammalian target of rapamycin complex 2; PDK1, 3-phosphoinositide-dependent kinase 1; PI3-K, phosphoinositide 3-kinase; PRAS40, proline-rich AKT substrate of 40 kDa; PX, phox homology; SGK3, serum and glucocorticoid inducible kinase 3; TSC2, tuberous sclerosis factor 2; PTEN, phosphatase and tensin homolog; mLST8, MTOR associated protein LST8 homolog; mSIN1, mitogen-activated protein kinase associated protein 1.