Serum- and Glucocorticoid-induced Protein Kinase 1 (SGK1) Is Regulated by Store-operated Ca2+ Entry and Mediates Cytoprotection against Necrotic Cell Death

Brickley, Deanna R.; Agyeman, Abena S.; Kopp, Richard F.; Hall, Benjamin; Harbeck, Mark; Belova, Larissa; Volden, Paul A.; Wu, Wei; Roe, Michael W.; Conzen, Suzanne D.

doi:10.1074/jbc.m113.507210

Cited by 14 publications

(19 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that Akt does not appear to be a relevant mediator of ATP generation downstream of PI(3)K (in the presence of oncogenic Ras) during ECM detachment, we assessed the contribution of SGK-1, another AGC family kinase known to operate downstream of PI(3)K. 6 SGK-1 shares significant sequence identity with Akt and has previously been linked to the regulation of glucose transporter localization. 6,[18][19][20] In our 10A HrasG12V and 10A KrasG12V cells, we see a decrease in SGK-1 activation upon PI(3)K inhibition as measured by phosphorylation status of Sek1 at serine 80 (Figure 1e), a canonical downstream SGK-1 target. 21 In addition, we observe an increase in the phosphorylation of Sek1 in the presence of oncogenic Ras mutations (Figure 1f).…”

Section: Resultsmentioning

confidence: 97%

See 1 more Smart Citation

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

et al. 2016

View full text Add to dashboard Cite

In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors. Cell Death and Differentiation (2016) 23, 1271-1282 doi:10.1038/cdd.2016 published online 26 February 2016 Cancer metastasis, the spread of cancer cells to distant parts of the body, accounts for~90% of cancer-related deaths and represents an inherently difficult clinical challenge.1,2 It has become clear that for successful metastasis to occur, cells must overcome a caspase-dependent cell death mechanism, anoikis, which is triggered by detachment from the extracellular matrix (ECM).3 In addition to anoikis evasion, cancer cells must also contend with anoikis-independent cellular alterations that can compromise cellular viability. 4 Chief among these alterations are metabolic deficiencies that are induced by ECM detachment. [5][6][7] These metabolic alterations involve deficiencies in ATP generation, elevated levels of reactive oxygen species, and the induction of autophagy. 6,8,9 Although recent studies have begun to unravel the strategies used by cancer cells to ameliorate metabolic deficiencies during ECM detachment, 10 the signal-transduction cascades responsible for regulating metabolism during ECM detachment in cancer cells remain almost entirely unexplored.The activation of oncogenic signaling pathways is critical to anchorage-independent growth and ultimately to the survival of a variety of distinct cancer cell types during ECM detachment. 4,11 Presumably, this oncogenic signaling is also necessary for resolving the aforementioned ECM-detachment-induced metabolic deficiencies. ErbB2 overexpression in mammary epithelial cells results in a stimulation of phosphatidylinositol (3)-kinase (PI(3)K)/Akt signaling to promote glucose uptake and ATP generation.6 These data raise the question as to how cancer cells that lack ErbB2 overexpression rectify metabolic deficiencies during ECM detachment. Does activation o...

show abstract

Section: Resultsmentioning

confidence: 97%

“…34 It is noteworthy that other investigators have discovered that SGK-1 can interact with proteins at the mitochondria and can inhibit the induction of necrotic cell death. 19,35 Our data implicating SGK-1 in ATP generation may provide additional insight into these connections between SGK-1 and mitochondrial integrity.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…As 1 subunit of ICRAC, Ca 2+ release‐activated Ca 2+ channel protein 1 (Orai1) was identified as being coexpressed with SGK1 protein in human endometrium and Ishikawa cells (73). Furthermore, SGK1 boosts SOCE activity by up‐regulating its pore‐forming subunit and its regulators Orai1/stromal interacting molecule 1 via phosphorylation and inactivation of the ubiquitin ligase neuronal precursor cell‐expressed, developmentally down‐regulated 4 ligase, which ubiquitinates Orai1 (73, 74), thereby mediating cellular Ca 2+ entry upon stimulation of multiple mitogenic factors‐aprerequisite for triggering cell proliferation (25, 69, 75, 76). Moreover, SGK1 invokes activation of NF‐κB, a transcription factor that is required for Orai1 and Orai1/stromal interacting molecule 1 transcription (73, 74).…”

Section: Involvement Of Sgk1 In Decidualizationmentioning

confidence: 99%

“…Moreover, SGK1 invokes activation of NF-kB, a transcription factor that is required for Orai1 and Orai1/stromal interacting molecule 1 transcription (73,74). Of interest, Brickley et al (76) suggested that the increasing influx of extracellular Ca 2+ through I CRAC up-regulates SGK1 transcription in human mammary epithelial cells, which, in turn, attenuates mitochondrial membrane hyperpolarization and subsequent cell death induced by Ca 2+ overloading. This positive feedback accentuates the effects of SGK1 on cell proliferation and survival.…”

Section: Sgk1 Promotes Cell Proliferation and Survival Of Deciduamentioning

confidence: 99%

Involvement of serum glucocorticoid‐regulated kinase 1 in reproductive success

Lou

Mao

et al. 2016

FASEB j.

View full text Add to dashboard Cite

Reproductive processes, in particular events that concern pregnancy, are fine-tuned to produce offspring. Reproductive success is of prime importance for the survival of every species. The highly conserved and ubiquitously expressed serum glucocorticoid-regulated kinase 1 (SGK1) was first implicated in infertility as a regulator of a Na channel. In this review, we emphasize the prominent role of SGK1 during early pregnancy: 1) balancing uterine luminal fluid secretion and reabsorption to aid blastocyst adhesion and to import nutrients and energy; 2) transducing signals from the blastocyst to the receptive endometrium; 3) inducing multiple genes that are involved in uterine receptivity and trophoblast invasion; 4) regulating cell differentiation and antioxidant defenses at the fetomaternal interface; and 5) contributing to the proliferation and survival of decidual stromal cells. Accordingly, SGK1 coordinates many cellular processes that are crucial to reproductive activities. Aberrant expression or function of SGK1 results in implantation failure and early pregnancy loss. Further investigation of the molecular mechanisms of the function of SGK1 might provide novel diagnostic tools and interventions for reproductive complications.-Lou, Y., Hu, M., Mao, L., Zheng, Y., Jin, F. Involvement of serum glucocorticoid-regulated kinase 1 in reproductive success.

show abstract

“…SGK-1 belongs to the AGC kinase family and is the sole C. elegans homologue of the mammalian Serum-and Glucocorticoid-inducible Kinase. Its expression is induced upon diverse stimuli, including overload of calcium [16], heat shock, oxidative or osmotic stress [17–19], besides of glucocorticoids, cytokines and growth factors [20, 21]. Its activation is dependent on PI3K and has been involved in response to oxidative stress and DNA damage, among others [22].…”

Section: Introductionmentioning

confidence: 99%

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

Hernando‐Rodríguez

Pérez-Jiménez

Rodríguez-Palero

et al. 2019

Preprint

View full text Add to dashboard Cite

13 14 -2 -Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar 15 effect on lifespan. While PHB depletion shortens lifespan of wild type animals, it 16 enhances longevity of a plethora of metabolically compromised mutants, 17 including target of rapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Here, 18 we show that sgk-1 mutants have impaired mitochondrial homeostasis, 19 lipogenesis, yolk formation and autophagy flux due to alterations in membrane 20 lipid and sterol homeostasis. Remarkably, all these features are suppressed by 21 PHB depletion. Lifespan analysis shows that autophagy and the mitochondrial 22 unfolded protein response (UPR mt ), but not mitophagy, are required for the 23 enhanced longevity caused by PHB depletion in sgk-1 mutants. We hypothesize 24 that UPR mt induction upon PHB depletion extends lifespan of sgk-1 mutants 25 through autophagy. Our results strongly suggest that PHB depletion suppresses 26 the autophagy defects of sgk-1 mutants by altering membrane lipid composition 27 at ER-mitochondria contact sites, where TORC2 localizes. 28 29 93 mitochondria-associated endoplasmic reticulum (ER) membranes (MAM).94 95 -6 - Results 96Prohibitin depletion suppresses the altered mitochondrial structure and 97 function of sgk-1 mutants 98In C. elegans, loss of function of SGK-1 causes a delay in development (Jones et al., 992009) as well as reduced brood and body size (Soukas et al., 2009). These phenotypes 100 are consistent with phenotypes observed in mitochondrial mutants (Dillin et al., 2002). In 101 addition, worms lacking the TORC2 component RICT-1 or the downstream kinase SGK-102 1, have an induced mitochondrial unfolded protein response (UPR mt ) (Gatsi et al., 2014). 103We analyzed whether mitophagy, another mitochondrial quality control mechanism, 104 might be activated in sgk-1 deletion mutants using a mitophagy reporter based on PINK-105 1 protein (Kirienko et al., 2015). PINK-1 is a serine threonine protein kinase that, when 106 mitochondria are depolarized, accumulates in the outer mitochondrial membrane and 107 targets mitochondria for selective autophagy (Narendra and Youle, 2011; Palikaras et 108 al., 2015). We observed that depletion of sgk-1 increased PINK-1 protein levels ( Figure 109 1A). Similarly, PINK-1 protein levels increased upon depletion of phb-1 or atfs-1, the key 110 UPR mt regulator ( Figure 1A), confirming that sgk-1 mutants suffer from mitochondrial 111 stress. 112To better define the mitochondrial defect of sgk-1 deletion mutants we performed 113 transmission electron microscopy (TEM) analysis. Mitochondria in sgk-1 mutants were 114 swollen, and bigger compared to wild type worms in all tissues analyzed (hypodermis, 115 muscle and intestine) at both, day one and day five of adulthood ( Figure 1B and Figure 116 S1A, respectively). In contrast to previous observations (Zhou et al., 2019), no obvious 117 mitochondrial fragmentation or severe cristae defects in the intestine were observed in 118 the TEM sections analyzed. 119-7 -To ...

show abstract

Serum- and Glucocorticoid-induced Protein Kinase 1 (SGK1) Is Regulated by Store-operated Ca2+ Entry and Mediates Cytoprotection against Necrotic Cell Death

Cited by 14 publications

References 65 publications

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

Involvement of serum glucocorticoid‐regulated kinase 1 in reproductive success

Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy

Contact Info

Product

Resources

About