Protein Kinase SGK Mediates Survival Signals by Phosphorylating the Forkhead Transcription Factor FKHRL1 (FOXO3a)

Abstract

Serum-and glucocorticoid-inducible kinases (SGKs) form a novel family of serine/threonine kinases that are activated in response to a variety of extracellular stimuli. SGKs are related to Akt (also called PKB), a serine/threonine kinase that plays a crucial role in promoting cell survival. Like Akt, SGKs are activated by the phosphoinositide-3 kinase (PI3K) and translocate to the nucleus upon growth factor stimulation. However the physiological substrates and cellular functions of SGKs remained to be identified. We hypothesized that SGKs regulate cellular functions in concert with Akt by phosphorylating common targets within the nucleus. The best-characterized nuclear substrates of Akt are transcription factors of the Forkhead family. Akt phosphorylates Forkhead transcription factors such as FKHRL1, leading to FKHRL1's exit from the nucleus and the consequent shutoff of FKHRL1 target genes. We show here that SGK1, like Akt, promotes cell survival and that it does so in part by phosphorylating and inactivating FKHRL1. However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. These findings indicate that SGK acts in concert with Akt to propagate the effects of PI3K activation within the nucleus and to mediate the biological outputs of PI3K signaling, including cell survival and cell cycle progression.Serum-and glucocorticoid-induced kinases (SGKs) belong to a new family of serine/threonine kinases that are regulated at both the transcriptional and posttranslational levels by external stimuli. The mRNA encoding SGK1, the best-studied member of the SGK family, is rapidly induced in response to a variety of stimuli, including growth factors (51, 52), steroid and peptide hormones (3, 51, 52), cytokines (15, 50), changes in cell volume (49), and brain injury (24).The SGK gene is conserved from yeast to human, and the SGK protein is expressed in a variety of tissues and cell lines in mammals (10, 51, 52). Although it has been proposed that SGK may play a role in cell cycle progression (8) or sodium homeostasis control (4, 12), the cellular functions of SGK are largely uncharacterized, and to date no in vivo SGK substrates have been identified.Within the protein kinase superfamily, SGK is closely related to Akt (also called PKB), another serine/threonine kinase that is activated in response to growth and survival factors and plays a critical role in promoting cell survival (16,20). Several recent reports have shown that growth and s...

Serum/glucocorticoid-induced protein kinase-1 facilitates androgen receptor-dependent cell survival

“…These data suggest that SGK-1 elimination leads to apoptosis, which is supported by previous reports. [26][27][28][29] Next, we confirmed that SGK-1 siRNA could induce apoptosis in another prostate cancer cell line. LNCaP cells were tested using a clonogenic assay.…”

“…Similar to Akt, SGK-1 has been shown to be a cellular survival factor. [26][27][28][29] Therefore, we examined the role of SGK-1 in AR-dependent survival of prostate cancer cells. First, we tested if eliminating SGK-1 expression induces apoptosis.…”

“…This effect leads to increased I kappa B-alpha (IkB-a) phosphorylation and nuclear factor-kB (NF-kB)-dependent survival, 28 and also suppresses FOXO3 transactivation. 29 Therefore, we tested to see if IkB-a phosphorylation was altered after AR silencing or SGK-1 overexpression. As shown in Figure 5d, IkB-a phosphorylation was largely reduced in LNCaP/PURO cells after AR silencing compared to the control (lane 2 versus lane 1), which was associated with SGK-1 downregulation.…”

“…26,27,29,36 A recent study discovered a novel mechanism that SGK-1 promotes NF-kB survival pathway by activating IKKb. 28 In this study, we found that in AR Figure 7 Proposed mechanism for SGK-1 expression in AR-dependent survival.…”

“…The human prostate cancer LNCaP and LAPC-4 cells and their culture conditions were described previously. 12,33,[38][39][40] LAPC-4/ SGK1 and LNCaP/SGK1 sublines were established by stably infecting the parental cells with a retrovirus vector (pMSCV-puro-SGK1) 29 bearing the rat sgk1 gene. The control subline LAPC-4/Puro and LNCaP/Puro were established when an empty vector was used.…”