The phosphatidylinositol 3' kinase (PI3K)-signaling pathway plays a critical role in a variety of cellular responses such as modulation of cell survival, glucose homeostasis, cell division, and cell growth. PI3K generates important lipid second messengers-phosphatidylinositides that are phosphorylated at the 3' position of their inositol ring head-group. These membrane restricted lipids act by binding with high affinity to specific protein domains such as the pleckstrin homology (PH) domain. Effectors of PI3K include molecules that harbor such domains such as phosphoinositide-dependent kinase (PDK1) and protein kinase B (PKB), also termed Akt. The mammalian genome encodes three different PKB genes (alpha, beta, and gamma; Akt1, 2, and 3, respectively) and each is an attractive target for therapeutic intervention in diseases such as glioblastoma and breast cancer. A second family of three protein kinases, termed serum and glucocorticoid-regulated protein kinases (SGKs), is structurally related to the PKB family including regulation by PI3K but lack a PH domain. However, in addition to PH domains, a second class of 3' phosphorylated inositol phospholipid-binding domains exists that is termed Phox homology (PX) domain: this domain is found in one of the SGKs (SGK3). Here, we summarize knowledge of the three SGK isoforms and compare and contrast them to PKB with respect to their possible importance in cellular regulation and potential as therapeutic targets.

Serum and glucocorticoid-regulated kinases (SGKs) form a family of serine/threonine protein kinases that exhibit structural and sequence similarity to the protein kinase B (PKB)/Akt family. The major difference between these two families is the absence of a lipid-binding, pleckstrin homology domain in the SGKs. Despite the absence of the pleckstrin homology domain, activation of the three human isoforms is, like PKB, dependent upon the phosphatidylinositol 3-kinase (PI3K) pathway that is induced by growth factors and mitogens. Full-length SGK3 contains a complete Phox homology (PX) domain that targets the protein to endosomes. Both a functional PX domain and PI3K activation are necessary for phosphorylation of SGK3 at two regulatory sites (Thr-320 and Ser-486) and subsequent induction of kinase activity. PDK1 phosphorylates endosome-associated SGK3 at Thr-320, whereas diversion of SGK3 to the plasma membrane, where PDK1 normally activates PKB, interferes with PDK1 phosphorylation of SGK3. A chimeric protein in which the carboxyl-terminal hydrophobic motif (HM) of SGK3 has been exchanged for the HM of PRK2 is constitutively active. Finally, we demonstrate that SGK3 activation becomes PX domain-independent once the HM is phosphorylated. Taken together, these data indicate that the targeting of SGK3 to endosomes, mediated by its PX domain, is essential for proper SGK3 activation, likely due to co-localization of SGK3 with an endosomal, PI3K-dependent and staurosporine-sensitive HM kinase. Serum and glucocorticoid-regulated kinases (SGKs)2 comprise a novel family of three serine/threonine protein kinases that show extensive sequence homology to the kinase domain of the protein kinase B (PKB)/Akt family. SGK1 was identified in a differential screen for glucocorticoid-inducible transcripts in a rat mammary tumor cell line (1). Three isoforms of SGK have been identified in humans and are encoded by distinct genes: SGK1, SGK2, and SGK3 (2, 3). All isoforms are posttranslationally modified by phosphorylation and are regulated downstream of phosphatidylinositol 3Ј-kinase (PI3K) (2-4). Similar to PKB, the SGK isoforms are phosphorylated and activated by phosphoinositide-dependent kinase-1 (PDK1) at a threonine residue in the T-loop analogous to Thr-308 of PKB␣. The PI3K pathway is involved in several important cellular functions, including insulin action, cell division, cell growth, and cell survival, and dysregulation of the pathway is implicated in a variety of diseases, including cancer and diabetes.One major structural difference between PKBs and SGKs is the absence of a phospholipid-binding pleckstrin homology domain near the amino terminus of the SGKs. This domain binds the 3,4,5Ј-triphosphorylated phosphoinositide (PIP 3 ) lipid product of PI3K and causes recruitment of PKB and PDK-1 to the plasma membrane, the site of PIP 3 synthesis. The initial isolate of a human SGK3 cDNA by sequence homology to SGK1 lacked a lipid binding domain. The mouse homologue of SGK3, termed cytokine-independent survival kinase (CISK), w...