Journal articles: 'SgK223'

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O'Rourke, Rachelle L., and Roger J. Daly. "The pseudokinases SgK269 and SgK223: A novel oncogenic alliance in human cancer." Cell Adhesion & Migration 12, no. 6 (December 21, 2017): 524–28. http://dx.doi.org/10.1080/19336918.2017.1394570.

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Liu, Ling, Yu Wei Phua, Rachel S. Lee, Xiuquan Ma, Yiping Jenkins, Karel Novy, Emily S. Humphrey, et al. "Homo- and Heterotypic Association Regulates Signaling by the SgK269/PEAK1 and SgK223 Pseudokinases." Journal of Biological Chemistry 291, no. 41 (August 16, 2016): 21571–83. http://dx.doi.org/10.1074/jbc.m116.748897.

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Lopez, Mitchell L., Megan Lo, Jennifer E. Kung, Małgorzata Dudkiewicz, Gwendolyn M. Jang, John Von Dollen, Jeffrey R. Johnson, Nevan J. Krogan, Krzysztof Pawłowski, and Natalia Jura. "PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization." Proceedings of the National Academy of Sciences 116, no. 31 (July 16, 2019): 15495–504. http://dx.doi.org/10.1073/pnas.1906360116.

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Members of the New Kinase Family 3 (NKF3), PEAK1/SgK269 and Pragmin/SgK223 pseudokinases, have emerged as important regulators of cell motility and cancer progression. Here, we demonstrate that C19orf35 (PEAK3), a newly identified member of the NKF3 family, is a kinase-like protein evolutionarily conserved across mammals and birds and a regulator of cell motility. In contrast to its family members, which promote cell elongation when overexpressed in cells, PEAK3 overexpression does not have an elongating effect on cell shape but instead is associated with loss of actin filaments. Through an unbiased search for PEAK3 binding partners, we identified several regulators of cell motility, including the adaptor protein CrkII. We show that by binding to CrkII, PEAK3 prevents the formation of CrkII-dependent membrane ruffling. This function of PEAK3 is reliant upon its dimerization, which is mediated through a split helical dimerization domain conserved among all NKF3 family members. Disruption of the conserved DFG motif in the PEAK3 pseudokinase domain also interferes with its ability to dimerize and subsequently bind CrkII, suggesting that the conformation of the pseudokinase domain might play an important role in PEAK3 signaling. Hence, our data identify PEAK3 as an NKF3 family member with a unique role in cell motility driven by dimerization of its pseudokinase domain.

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Glenn, Martha J., Rosalie G. Waller, and Nicola J. Camp. "Exome Sequencing in a Family with Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma and Autoimmune Disease Uncovers Potential Germline Risk-Alleles." Blood 124, no. 21 (December 6, 2014): 5629. http://dx.doi.org/10.1182/blood.v124.21.5629.5629.

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Abstract We identified a Caucasian family with dense distribution of B-cell non-Hodgkin lymphoma (NHL) and autoimmune disease (Figure 1). Within the family, three siblings and their mother have B-cell NHL (three with chronic lymphocytic leukemia [CLL]; one with mantle cell lymphoma [MCL]), and four family members have autoimmune diseases (rheumatoid arthritis or multiple sclerosis). In addition, two family members have melanoma. To investigate the genetic factors involved in B-cell NHL in this family, we exome sequenced nine individuals, including two unaffected spouses as technical-artifact controls. Following best-practice guidelines, we performed joint variant calling, including an additional 135 European 1000Genome exomes as a set of background controls. Figure 1 Figure 1. After variant quality control, a total of 676,137 sequence variants were identified. We also performed individual genotype quality control based on a minimum read depth of 10 and genotype quality of 40, resulting in 554,690 variants. For our initial prioritization, we required that variants be: absent in the spouse controls, have minor allele frequency (MAF) â‰¤ 0.05 in the 1000Genome exomes, and be shared by all four B-cell NHL cases. This resulted in 73 variants of potential interest. Of the 73 variants, seven were predicted to be damaging by either PROVEAN or SIFT, two by both algorithms and by PolyPhen2. These two potentially damaging variants reside in the genes CCDC144A and RRS1. The gene CCDC144A is located at chromosome 17p11.2, a known breakpoint region of the 17p deletion often seen in CLL tumor cells. The variant identified in this gene was rare (MAF = 0.001 in the NHLBI Exome Sequencing Project [ESP]) and was also seen in two additional family members (one with rheumatoid arthritis; a second with rheumatoid arthritis and melanoma). The gene RRS1 is located at chromosome 8q13.1, and has been shown to be important for proper chromosomal organization during mitosis. The variant identified in this gene was relatively rare (MAF = 0.041 in ESP) and was seen in the same, two additional family members. Of the remaining five variants predicted damaging by only one algorithm, of interest were two variants in the SGK223 gene on chromosome 8p23.1. SGK223 is a kinase and a component in the BCR-ABL1 signaling network that is present in most chronic myelogenous leukemia cases and a quarter of adult acute lymphoblastic leukemia cases. Both of the variants in SGK223 were also seen in three additional family members (one with rheumatoid arthritis; a second with rheumatoid arthritis and melanoma; a third with melanoma). In addition to prioritization by predicted function of coding variants, we explored the 73 variants for overlap with findings from published germ-line investigations of B-cell NHL. This identified one variant in the ACOXL gene at chromosome 2q13. The variant is relatively rare (MAF = 0.017 in dbSNP) and lies in the same gene and intron (17,016 base pairs upstream) as rs13401811, the associated SNP (p = 2.08 x 10-18) reported in a genomewide association study (GWAS) for CLL. Our ongoing analyses and prioritization of the variants in this extraordinary family reveal overlap with signals coming from GWAS studies and suggest some potentially damaging variants in genes not previously implicated in NHL. The potential risk-alleles identified in our preliminary findings could shed new light about the genes and genetic factors involved in NHL. Disclosures No relevant conflicts of interest to declare.

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Rodrigues, Gisele O. L., Wenqing Li, Sarah Cramer, Livia W. Campos, Priscila P. Zenatti, Angelo A. B. A. Laranjeira, Julie A. Hixon, et al. "Identification of Genetic Alterations Associated with Mutant IL7Ralpha in T-ALL." Blood 128, no. 22 (December 2, 2016): 5272. http://dx.doi.org/10.1182/blood.v128.22.5272.5272.

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Abstract The IL7/IL7R mediated signaling is essential for normal development and homeostasis of T cell precursors. Early studies have shown that around 10% of patients with Acute lymphoblastic leukemia T cell (T-ALL) have mutations in the alpha chain of the receptor for IL7 (IL-7Ralpha) driving constitutive signaling via JAK1 and independent of IL-7, gamma-chain or JAK3. Some genetic changes are important factors to initiate leukemia, but in many cases these changes are insufficient to achieve the complete leukemic phenotype, suggesting that collaborative oncogenic mutations may be present. To identify candidate mutations that work in collaboration with the oncogenic IL7R, we performed exome sequencing and SNP-CNV-Array assay on a group of eight primary T-ALL samples carrying the IL7R mutation (T-ALL-IL7Rmut). The microarray was performed using Cytoscan HD - Affymetrix and CNVs were detected by ChAs software, version 2.0.1.2. For exome sequencing we used Illumina Hiseq2000 platform and Agilent SureSelect V4 51M Capture kit (mean sequencing depths of 80X / 50X for leukemia and remission samples, respectively). Somatic Single Nucleotide Variants (SNVs) and Small Insertion/Deletion (InDels) were detected using VarScan, and mutations were functionally annotated using ANNOVAR. All somatic mutations detected were manually curated. We found 17 genes recurrently mutated (in ≥ 2 cases) and chose five of them for further analyses due to their previous involvement in ALL (PHF6, RB1, CTCF, SGK223 and DNM2). Ongoing experiments are being conducted to determine whether these recurrent mutations can collaborate functionally with mutIL7R by co-transfection into immature murine thymocytes, transplanting into mice and determining incidence of leukemia. Disclosures No relevant conflicts of interest to declare.

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KOBAYASHI, Takayasu, Maria DEAK, Nick MORRICE, and Philip COHEN. "Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase." Biochemical Journal 344, no. 1 (November 8, 1999): 189–97. http://dx.doi.org/10.1042/bj3440189.

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The catalytic domain of serum- and glucocorticoid-induced protein kinase (SGK) is 54% identical with protein kinase B (PKB) and, like PKB, is activated in vitro by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and in vivo in response to signals that activate phosphatidylinositol (PI) 3-kinase. Here we identify two novel isoforms of SGK, termed SGK2 and SGK3, whose catalytic domains share 80% amino acid sequence identity with each other and with SGK (renamed SGK1). Like SGK1, the mRNA encoding SGK3 is expressed in all tissues examined, but SGK2 mRNA is only present at significant levels in liver, kidney and pancreas and, at lower levels, in the brain. The levels of SGK2 mRNA in H4IIE cells and SGK3 mRNA in Rat2 fibroblasts are not increased by stimulation with serum or dexamethasone, whereas the level of SGK1 mRNA is increased greatly. SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr193 and Thr253 respectively, the residues equivalent to the Thr in the ‘activation loop’ of PKB that is targeted by PDK1. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser356 and Ser419 respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. Like SGK1, SGK2 and SGK3 are activated 5-fold via a phosphorylation mechanism when cells are exposed to H2O2 but, in contrast with SGK1, activation is only suppressed partially by inhibitors of PI 3-kinase. SGK2 and SGK3 are activated to a smaller extent by insulin-like growth factor-1 (2-fold) than SGK1 (5-fold). Like PKB and SGK1, SGK2 and SGK3 preferentially phosphorylate Ser and Thr residues that lie in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr motifs.

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He, Peijian, Sei-Jung Lee, Songbai Lin, Ursula Seidler, Florian Lang, Geza Fejes-Toth, Aniko Naray-Fejes-Toth, and C. Chris Yun. "Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids." Molecular Biology of the Cell 22, no. 20 (October 15, 2011): 3812–25. http://dx.doi.org/10.1091/mbc.e11-04-0328.

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Na+/H+ exchanger 3 (NHE3) is the major Na+ transporter in the intestine. Serum- and glucocorticoid-induced kinase (SGK) 1 interacts with NHE regulatory factor 2 (NHERF2) and mediates activation of NHE3 by dexamethasone (Dex) in cultured epithelial cells. In this study, we compared short-term regulation of NHE3 by Dex in SGK1-null and NHERF2-null mice. In comparison to wild-type mice, loss of SGK1 or NHERF2 significantly attenuated regulation of NHE3 by Dex but did not completely obliterate the effect. We show that transfection of SGK2 or SGK3 in PS120 cells resulted in robust activation of NHE3 by Dex. However, unlike SGK1 or SGK2, SGK3 rapidly activated NHE3 within 15 min of Dex treatment in both PS120 and Caco-2bbe cells. Immunofluorescence analysis showed that SGK3 colocalized with NHE3 in recycling endosomes, whereas SGK1 and SGK2 were diffusely distributed. Mutation of Arg-90 of SGK3 disrupted the endosomal localization of SGK3 and delayed NHE3 activation. Activation of SGK3 and NHE3 by Dex was dependent on phosphoinositide 3-kinase (PI3K) and phosphoinositide-dependent kinase 1 (PDK1), and Dex induced translocation of PDK1 to endosomes. Our study identifies SGK3 as a novel endosomal kinase that acutely regulates NHE3 in a PI3K-dependent mechanism.

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Kim, Jeongeun, Donghee Kim, Hyunho Jung, Jinho Lee, and Victor Sukbong Hong. "Identification and Kinetic Characterization of Serum- and Glucocorticoid-Regulated Kinase Inhibitors Using a Fluorescence Polarization–Based Assay." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 5 (March 30, 2021): 655–62. http://dx.doi.org/10.1177/24725552211002465.

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The serum- and glucocorticoid-regulated kinase (SGK) family consists of three isoforms (SGK1, SGK2, and SGK3) that have been implicated in the regulation of tumor growth, metastasis, autophagy, and epithelial ion transport. SGK1 and SGK3 play essential roles in protein kinase B (AKT or PKB)-independent phosphoinositide 3-kinases (PI3K)-mediated tumorigenesis, as evidenced by the significantly elevated expression levels of SGK1 and SGK3 in many cancers, including prostate cancer, colorectal carcinoma, estrogen-dependent breast cancer, and glioblastoma. Therefore, SGK is a potential target for anticancer therapy. A small kinase-focused library comprising 160 compounds was screened against SGK1 using a fluorescence polarization–based kinase assay that yielded a Z’-factor of 0.82. Among the 39 compounds obtained as initial hits in a primary screen, 12 compounds contained the thiazolidine-2,4-dione scaffold. The inhibitory mechanisms of the most potent hit, KMU010402, were further investigated using kinetic analyses, followed by determination of the inhibition constants for SGK1, SGK2, and SGK3. Molecular modeling was used to propose a potential binding mode of KMU010402 to SGK1.

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Bilanges, Benoit, and Bart Vanhaesebroeck. "Cinderella finds her shoe: the first Vps34 inhibitor uncovers a new PI3K–AGC protein kinase connection." Biochemical Journal 464, no. 2 (November 14, 2014): e7-e10. http://dx.doi.org/10.1042/bj20141218.

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Class II/III PI3Ks (phosphoinositide 3-kinases) produce the PtdIns(3)P lipid that is involved in intracellular vesicular trafficking. In contrast with class I PI3Ks, the potential signalling roles of class II/III PI3Ks are poorly understood. In a recent article in the Biochemical Journal, Bago and co-workers report that Vps34 (vacuolar protein sorting 34), the only class III PI3K, controls the activity of SGK3 (serum- and glucocorticoid-regulated protein kinase 3). Like other AGC kinases, the SGKs (SGK1, SGK2 and SGK3) are activated by dual phosphorylation. Unlike its cousins SGK1 and SGK2, SGK3 contains a PtdIns(3)P-binding domain, providing an additional element of regulation. The study by Bago et al. characterizes and makes extensive use of a Novartis Vps34 inhibitor (VPS34-IN1) that inhibits this PI3K isoform with nanomolar potency, without affecting other lipid kinases or more than 300 protein kinases. The authors show that this compound very rapidly reduced PtdIns(3)P levels at the endosome with concomitant loss of SGK3 phosphorylation. Co-inhibition of class I PI3Ks led to a further reduction in SGK3 activity, indicating that class I PI3Ks may also regulate SGK3 activity through an additional, currently unknown, mechanism. It remains to be assessed whether the novel PI3K–protein kinase connection established by this study is subject to acute cellular stimulation or is part of a constitutive housekeeping function. VPS34-IN1 will provide a useful tool to decipher the kinase-dependent functions of Vps34, with acute changes in SGK3 phosphorylation and subcellular localization being new biomarkers of Vps34 activity.

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Pao, Alan C., James A. McCormick, Hongyan Li, John Siu, Cedric Govaerts, Vivek Bhalla, Rama Soundararajan, and David Pearce. "NH2 terminus of serum and glucocorticoid-regulated kinase 1 binds to phosphoinositides and is essential for isoform-specific physiological functions." American Journal of Physiology-Renal Physiology 292, no. 6 (June 2007): F1741—F1750. http://dx.doi.org/10.1152/ajprenal.00027.2007.

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Serum and glucocorticoid regulated kinase 1 (SGK1) has been identified as a key regulatory protein that controls a diverse set of cellular processes including sodium (Na+) homeostasis, osmoregulation, cell survival, and cell proliferation. Two other SGK isoforms, SGK2 and SGK3, have been identified, which differ most markedly from SGK1 in their NH2-terminal domains. We found that SGK1 and SGK3 are potent stimulators of epithelial Na+ channel (ENaC)-dependent Na+ transport, while SGK2, which has a short NH2 terminus, is a weak stimulator of ENaC. Further characterization of the role of the SGK1 NH2 terminus revealed that its deletion does not affect in vitro kinase activity but profoundly limits the ability of SGK1 either to stimulate ENaC-dependent Na+ transport or inhibit Forkhead-dependent gene transcription. The NH2 terminus of SGK1, which shares sequence homology with the phosphoinositide 3-phosphate [PI( 3 )P] binding domain of SGK3, binds phosphoinositides in protein lipid overlay assays, interacting specifically with PI( 3 )P, PI( 4 )P, and PI( 5 )P, but not with PI( 3 , 4 , 5 )P3. Moreover, a point mutation that reduces phosphoinositide binding to the NH2 terminus also reduces SGK1 effects on Na+ transport and Forkhead activity. These data suggest that the NH2 terminus, although not required for PI 3-kinase-dependent modulation of SGK1 catalytic activity, is required for multiple SGK1 functions, including stimulation of ENaC and inhibition of the proapoptotic Forkhead transcription factor. Together, these observations support the idea that the NH2-terminal domain acts downstream of PI 3-kinase-dependent activation to target the kinase to specific cellular compartments and/or substrates, possibly through its interactions with a subset of phosphoinositides.

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YJ, Zhang, M. Xie, Li CY, G. Wu, and Peng DL. "Impacts of the transgenic CrylAc and CpTI insect-resistant cotton SGK321 on selected soil enzyme activities in the rhizosphere." Plant, Soil and Environment 60, No. 9 (September 8, 2014): 401–6. http://dx.doi.org/10.17221/349/2014-pse.

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Transgenic CrylAc and CpTI insect-resistant cotton SGK321 is widely adopted for many years in several regions of China, however the understanding of its potential effects on soil enzyme activities is not studied. The impacts of transgenic cotton SGK321 on dehydrogenase, urease and phosphatase activities in rhizosphere soil were investigated in a two-year field study in Northern China. Rhizosphere soil enzyme activities between transgenic cotton SGK321 and its non-transgenic parental cotton Shiyuan 321 were found to differ at senescence. However compared to the plant growth stages and cotton cultivar, the impacts of the transgenic trait were minor or transient. The principal component analysis also showed no significant or minor difference in the activities of dehydrogenase, urease and phosphatase in the rhizosphere soil of transgenic cotton SGK321 and its counterpart. Our results indicated that the transgenic cotton SGK321 has no apparent impact on dehydrogenase, urease and phosphatase activities in rhizosphere soil.

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YJ, Zhang, M. Xie, and Peng DL. "Effects of the transgenic CrylAc and CpTI insect-resistant cotton SGK321 on rhizosphere soil microorganism populations in northern China." Plant, Soil and Environment 60, No. 6 (June 2, 2014): 285–89. http://dx.doi.org/10.17221/192/2014-pse.

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Transgenic CrylAc and CpTI insect-resistant cotton SGK321 has been widely adopted for many years in several regions of China, however the understanding of its potential effects on soil microorganisms is limited. The impact of transgenic cotton SGK321 on microorganism populations in rhizosphere soil was investigated. The numbers of bacteria, fungi, and actinomycetes were measured by counting colony-forming units after incubation on appropriate medium in a two-year field study in the northern China. Rhizosphere soil microorganism populations between transgenic cotton SGK321 and its non-transgenic parental cotton or conventional cotton were different at some plant growth stages and/or in some years. However compared to the plant growth stage and cotton cultivar, the impacts of the transgenic trait were slight or transient. The principal component analysis also showed no significant or minor difference in the numbers of bacteria, fungi, and actinomycetes in rhizosphere soil between transgenic cotton SGK321 and its non-transgenic parental cotton. These results suggest that the transgenic cotton SGK321 has no apparent impact on microorganism populations in rhizosphere soil.

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Cicenas, Jonas, Edita Meskinyte-Kausiliene, Vigilijus Jukna, Arnas Rimkus, Jokubas Simkus, and Diana Soderholm. "SGK1 in Cancer: Biomarker and Drug Target." Cancers 14, no. 10 (May 12, 2022): 2385. http://dx.doi.org/10.3390/cancers14102385.

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Serum- and glucocorticoid-regulated kinases (SGKs) are members of the AGC family of serine/threonine kinases, consisting of three isoforms: SGK1, SGK2, and SGK3. SGK1 was initially cloned as a gene transcriptionally stimulated by serum and glucocorticoids in rat mammary tumor cells. It is upregulated in some cancers and downregulated in others. SGK1 increases tumor cell survival, adhesiveness, invasiveness, motility, and epithelial to mesenchymal transition. It stimulates tumor growth by mechanisms such as activation of K+ channels and Ca2+ channels, Na+/H+ exchanger, amino acid and glucose transporters, downregulation of Foxo3a and p53, and upregulation of β-catenin and NFκB. This chapter focuses on major aspects of SGK1 involvement in cancer, its use as biomarker as well as potential therapeutic target.

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Oshima, Koichi, Hossein Khiabanian, Ana Carolina da Silva Almeida, Gannie Tzoneva, Francesco Abate, Alberto Ambesi-Impiombato, Marta Sanchez-Martin, et al. "Mutational Landscape, Clonal Evolution Patterns and Role of RAS Mutations in Relapsed Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 4068. http://dx.doi.org/10.1182/blood.v128.22.4068.4068.

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Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children. Altogether 90% of pediatric ALL patients achieve a complete hematologic remission with current high dose combination chemotherapy and 80% of them remain leukemia free. However, the outcome for patients showing refractory disease or those whose leukemia relapses after an initial transient response remains disappointingly poor with cure rates of less than 40%. To investigate genetic drivers of relapse and resistance and explore the specific roles of clonal evolution in disease progression and relapse here we performed whole-exome sequence analysis of matched diagnosis, germline (remission) and relapse DNA samples in a panel of 55 pediatric ALL patients including 33 T-cell ALLs and 22 B-cell precursor ALLs. These analyses identified an average of 9 mutations present in diagnostic samples and 17 mutations in relapsed leukemia DNAs. Phylogenetic tree analysis for each of the 48 cases with optimal variant call parameters analyzing their clonal evolution dynamics during disease progression, combined with whole genome sequencing of targeted samples with low exonic mutation input, showed that branched evolution in which relapse clones contain some, but not all genetic lesions present in the major clone at diagnosis as the primary mechanism driving tumor progression and relapse present in 45/48 (94%) cases. In addition, and consistent with previous reports we identified the presence of chemotherapy associated mutations in NT5C2 (10/55), TP53 (3/55), CREBBP (4/55) and the NR3C1 glucocorticoid receptor gene (2/55). However, and most strikingly, 23/27 (85%) recurrently mutated genes in this series with mutations preferentially selected or retained at the time of relapse (mutation never lost in the relapse clone) were not implicated in relapse ALL before (HTR3A, MED12, USP9X, CACNA1H, ODZ3, AACS, SAMD4A, ANO5, PAPPA, NAALADL2, HIST3H2A, FZD7, TBX15, NEB, GREB1L, PLXNA4, SGK223, TSC1, PTPRG, FGF10, SYCP2, TRPM3 and EYS). A branched pattern of genetic evolution and the presence of recurrent mutations selected at relapse support that chemotherapy imposes a strong Darwinian genetic selection in leukemic cell populations. In this context it is worth noting that RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, while in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Most notably, and in agreement with this hypothesis, inducible expression of mutant KRAS in human ALL lines demonstrate that oncogenic KRAS G12D induces methotrexate resistance, but also improves leukemia response to vincristine; a phenotype perfectly recapitulated in a isogenic ALL leukemia model generated from a conditional inducible Kras G12D knockin mice. Mechanistically, KRAS G12 expression induces MAPK dependent abrogation of methotrexate induced apoptosis. Moreover, Kras mutant tumors show enhanced G2/M cell cycle arrest and apoptosis upon spindle poisoning with vincristine, a phenotype linked with increased PLK phosphorylation and transcriptional down-regulation of mitotic genes. Finally clonal competition assays demonstrate that the differential response to methotrexate and vincristine in isogenic Kras wild type and Kras mutant ALL cells results in clonal dominance of Kras G12D populations in cultures treated with methotrexate, while Kras wild type cells are selected the context of vincristine treatment. In all these results show novel insight on the genetics and mechanisms of clonal selection, disease progression and relapse in ALL and demonstrate a previously unrecognized dual role of RAS mutations in chemotherapy response. Disclosures Loh: Abbvie: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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Palmada, M., M. Dieter, A. Speil, C. Böhmer, A. F. Mack, H. J. Wagner, K. Klingel, et al. "Regulation of intestinal phosphate cotransporter NaPi IIb by ubiquitin ligase Nedd4–2 and by serum- and glucocorticoid-dependent kinase 1." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 1 (July 2004): G143—G150. http://dx.doi.org/10.1152/ajpgi.00121.2003.

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Serum and glucocorticoid-inducible kinase 1 (SGK1) is highly expressed in enterocytes. The significance of the kinase in regulation of intestinal function has, however, remained elusive. In Xenopus laevis oocytes, SGK1 stimulates the epithelial Na+ channel by phosphorylating the ubiquitin ligase Nedd4–2, which regulates channels by ubiquitination leading to subsequent degradation of the channel protein. Thus the present study has been performed to explore whether SGK1 regulates transport systems expressed in intestinal epithelial cells, specifically type IIb sodium-phosphate (Na+-Pi) cotransporter (NaPi IIb). Immunohistochemistry in human small intestine revealed SGK1 colocalization with Nedd4–2 in villus enterocytes. For functional analysis cRNA encoding NaPi IIb, the SGK isoforms and/or the Nedd4–2 were injected into X. laevis oocytes, and transport activity was quantified as the substrate-induced current ( IP). Exposure to 3 mM phosphate induces an IP in NaPi IIb-expressing oocytes. Coinjection of Nedd4–2, but not the catalytically inactive mutant C938SNedd4–2, significantly downregulates IP, whereas the coinjection of S422DSGK1 markedly stimulates IP and even fully reverses the effect of Nedd4–2 on IP. The effect of S422DSGK1 on NaPi IIb is mimicked by wild-type SGK3 but not by wild-type SGK2, constitutively active T308D,S473DPKB, or inactive K127NSGK1. Moreover, S422DSGK1 and SGK3 phosphorylate Nedd4–2. In conclusion, SGK1 stimulates the NaPi IIb, at least in part, by phosphorylating and thereby inhibiting Nedd4–2 binding to its target. Thus the present study reveals a novel signaling pathway in the regulation of intestinal phosphate transport, which may be important for regulation of phosphate balance.

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Lang, Florian, Christoph Böhmer, Monica Palmada, Guiscard Seebohm, Nathalie Strutz-Seebohm, and Volker Vallon. "(Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms." Physiological Reviews 86, no. 4 (October 2006): 1151–78. http://dx.doi.org/10.1152/physrev.00050.2005.

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The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocorticoids). Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1–5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, β-catenin, nuclear factor κB). SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na+ retention and K+ elimination of the kidney, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na+/H+ exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. A common (∼5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.

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Zemtsova, Irina M., Nicole Heise, Henning Fröhlich, Syed M. Qadri, Yuliya Kucherenko, Krishna M. Boini, David Pearce, Ekaterina Shumilina, and Florian Lang. "Blunted IgE-mediated activation of mast cells in mice lacking the serum- and glucocorticoid-inducible kinase SGK3." American Journal of Physiology-Cell Physiology 299, no. 5 (November 2010): C1007—C1014. http://dx.doi.org/10.1152/ajpcell.00539.2009.

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Previous studies have shown that pharmacological inhibition of the phosphoinositol-3 (PI3) kinase disrupts the activation of mast cells. Through phosphoinositide-dependent kinase PDK1, PI3 kinase activates the serum- and glucocorticoid-inducible kinase 3 (SGK3). The present study explored the role of SGK3 in mast cell function. Mast cells were isolated and cultured from bone marrow (BMMCs) of gene-targeted mice lacking SGK3 ( sgk3 −/−) and their wild-type littermates ( sgk3 +/+). BMMC numbers in the ear conch were similar in both genotypes. Stimulation with IgE and cognate antigen triggered the release of intracellular Ca2+ and entry of extracellular Ca2+. Influx of extracellular Ca2+ but not Ca2+ release from intracellular stores was significantly blunted in sgk3 −/− BMMCs compared with sgk3 +/+ BMMCs. Antigen stimulation further led to a rapid increase of a K+-selective conductance in sgk3 +/+ BMMCs, an effect again blunted in sgk3 −/− BMMCs. In contrast, the Ca2+ ionophore ionomycin activated K+ currents to a similar extent in sgk3 −/− and in sgk3 +/+ BMMCs. β-Hexosaminidase release, triggered by antigen stimulation, was also significantly decreased in sgk3 −/− BMMCs. IgE-dependent anaphylaxis measured as a sharp decrease in body temperature upon injection of DNP-HSA antigen was again significantly blunted in sgk3 −/− compared with sgk3 +/+ mice. Serum histamine levels measured 30 min after induction of an anaphylactic reaction were significantly lower in sgk3 −/− than in sgk3 +/+ mice. In conclusion, both in vitro and in vivo function of BMMCs are impaired in gene targeted mice lacking SGK3. Thus SGK3 is critical for proper mast cell function.

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Grahammer, Florian, Ferruh Artunc, Diana Sandulache, Rexhep Rexhepaj, Björn Friedrich, Teut Risler, James A. McCormick, et al. "Renal function of gene-targeted mice lacking both SGK1 and SGK3." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 290, no. 4 (April 2006): R945—R950. http://dx.doi.org/10.1152/ajpregu.00484.2005.

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Serum- and glucocorticoid-inducible kinase (SGK) 1 and SGK3 share the ability to upregulate several ion channels, including the epithelial Na+ channel. Whereas SGK1 is under genomic control of mineralocorticoids and glucocorticoids, SGK3 is constitutively expressed. The SKG1-knockout ( sgk1−/−) mouse is seemingly normal when it is fed a standard diet, but its ability to retain NaCl is impaired when it is fed a salt-deficient diet. In the SGK3-knockout ( sgk3−/−) mouse fed standard and salt-deficient diets, hair growth is strikingly delayed but NaCl excretion is normal. Thus the possibility was considered that SGK1 and SGK3 could mutually replace each other, thus preventing severe NaCl loss in sgk1−/− and sgk3−/− mice. We crossed SGK1- and SGK3-knockout mice and compared renal electrolyte excretion of the double mutants ( sgk1−/−/ sgk3−/−) with that of their wild-type littermates ( sgk1+/+/ sgk3+/+). Similar to sgk3−/− mice, the sgk1−/−/ sgk3−/− mice display delayed hair growth. Blood pressure was slightly, but significantly ( P < 0.03), lower in sgk1−/−/ sgk3−/− (102 ± 4 mmHg) than in sgk1+/+/ sgk3+/+ (114 ± 3 mmHg) mice, a difference that was maintained in mice fed low- and high-salt diets. Plasma aldosterone concentrations were significantly ( P < 0.01) higher in sgk1−/−/ sgk3−/− than in sgk1+/+ sgk3+/+ mice fed control (511 ± 143 vs. 143 ± 32 pg/ml) and low-salt (1,325 ± 199 vs. 362 ± 145 pg/ml) diets. During salt depletion, absolute and fractional excretions of Na+ were significantly ( P < 0.01) higher in sgk1−/−/ sgk3−/− (1.2 ± 0.2 μmol/24 h g body wt, 0.12 ± 0.03%) than in sgk1+/+/ sgk3+/+ (0.4 ± 0.1 μmol/24 h g body wt, 0.04 ± 0.01%) mice. The sgk1−/−/ sgk3−/− mice share the delayed hair growth with sgk3−/− mice and the modestly impaired renal salt retention with sgk1−/− mice. Additional lack of the isoform kinase does not substantially compound the phenotype for either property.

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Friedrich, B., Y. Feng, P. Cohen, T. Risler, A. Vandewalle, S. Bröer, J. Wang, D. Pearce, and F. Lang. "The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel α,β,γ-ENaC." Pflügers Archiv - European Journal of Physiology 445, no. 6 (January 21, 2003): 693–96. http://dx.doi.org/10.1007/s00424-002-0993-8.

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Pao, Alan C., Aditi Bhargava, Francesca Di Sole, Raymond Quigley, Xinli Shao, Jian Wang, Sheela Thomas, et al. "Expression and role of serum and glucocorticoid-regulated kinase 2 in the regulation of Na+/H+ exchanger 3 in the mammalian kidney." American Journal of Physiology-Renal Physiology 299, no. 6 (December 2010): F1496—F1506. http://dx.doi.org/10.1152/ajprenal.00075.2010.

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Serum and glucocorticoid-regulated kinase 2 (sgk2) is 80% identical to the kinase domain of sgk1, an important mediator of mineralocorticoid-regulated sodium (Na+) transport in the distal nephron of the kidney. The expression pattern and role in renal function of sgk2 are virtually uncharacterized. In situ hybridization and immunohistochemistry of rodent kidney coupled with real-time RT-PCR of microdissected rat kidney tubules showed robust sgk2 expression in the proximal straight tubule and thick ascending limb of the loop of Henle. Sgk2 expression was minimal in distal tubule cells with aquaporin-2 immunostaining but significant in proximal tubule cells with Na+/H+ exchanger 3 (NHE3) immunostaining. To ascertain whether mineralocorticoids regulate expression of sgk2 in a manner similar to sgk1, we examined sgk2 mRNA expression in the kidneys of adrenalectomized rats treated with physiological doses of aldosterone together with the glucocorticoid receptor antagonist RU486. Northern blot analysis and in situ hybridization showed that, unlike sgk1, sgk2 expression in the kidney was not altered by aldosterone treatment. Based on the observation that sgk2 is expressed in proximal tubule cells that also express NHE3, we asked whether sgk2 regulates NHE3 activity. We heterologously expressed sgk2 in opossum kidney (OKP) cells and measured Na+/H+ exchange activity by Na+-dependent cell pH recovery. Constitutively active sgk2, but not sgk1, stimulated Na+/H+ exchange activity by >30%. Moreover, the sgk2-mediated increase in Na+/H+ exchange activity correlated with an increase in cell surface expression of NHE3. Together, these results suggest that the pattern of expression, regulation, and role of sgk2 within the mammalian kidney are distinct from sgk1 and that sgk2 may play a previously unrecognized role in the control of transtubular Na+ transport through NHE3 in the proximal tubule.

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Talarico, Cristina, Vincenzo Dattilo, Lucia D'Antona, Miranda Menniti, Cataldo Bianco, Francesco Ortuso, Stefano Alcaro, Silvia Schenone, Nicola Perrotti, and Rosario Amato. "SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition." Cellular Physiology and Biochemistry 39, no. 5 (2016): 1863–76. http://dx.doi.org/10.1159/000447885.

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The serum- and glucocorticoid-regulated kinase (SGK) family consists of three members, SGK1, SGK2 and SGK3, all displaying serine/threonine kinase activity and sharing structural and functional similarities with the AKT family of kinases. SGK1 was originally described as a key enzyme in the hormonal regulation of several ion channels and pumps. Over time, growing and impressive evidence has been accumulated, linking SGK1 to the cell survival, de-differentiation, cell cycle control, regulation of caspases, response to chemical, mechanical and oxidative injury in cancer models as well as to the control of mitotic stability. Much evidence shows that SGK1 is over-expressed in a variety of epithelial tumors. More recently, many contributions to the published literature demonstrate that SGK1 can mediate chemo-and radio-resistance during the treatment of various human tumors, both in vitro and in vivo. SGK1 appears therefore as a dirty player in the stress response to chemical and radio-agents, responsible of a selective advantage that favors the uncontrolled tumor progression and the selection of the most aggressive clones. The purpose of this review is the analysis of the literature describing SGK1 as central node of the cell resistance, and a summary of the possible strategies in the pharmacological targeting of SGK1.

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Wang, Yuanzhong, Dujin Zhou, Sheryl Phung, Selma Masri, David Smith, and Shiuan Chen. "SGK3 Is an Estrogen-Inducible Kinase Promoting Estrogen-Mediated Survival of Breast Cancer Cells." Molecular Endocrinology 25, no. 1 (January 1, 2011): 72–82. http://dx.doi.org/10.1210/me.2010-0294.

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Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a protein kinase of the AGC family of protein kinase A, protein kinase G, and protein kinase C and functions downstream of phosphatidylinositol 3-kinase (PI3K). Recent study revealed that SGK3 plays a pivotal role in Akt/protein kinase B independent signaling downstream of oncogenic PI3KCA mutations in breast cancer. Here we report that SGK3 is an estrogen receptor (ER) transcriptional target and promotes estrogen-mediated cell survival of ER-positive breast cancer cells. Through a meta-analysis on 22 microarray studies of breast cancer in the Oncomine database, we found that the expression of SGK3 is significantly higher (5.7-fold, P < 0.001) in ER-positive tumors than in ER-negative tumors. In ER-positive breast cancer cells, SGK3 expression was found to be induced by 17β-estradiol (E2) in a dose- and time-dependent manner, and the induction of SGK3 mRNA by E2 is independent of newly synthesized proteins. We identified two ERα-binding regions at the sgk3 locus through chromatin immunoprecipitation with massively parallel DNA sequencing. Promoter analysis revealed that ERα stimulates the activity of sgk3 promoters by interaction with these two ERα-binding regions on E2 treatment. Loss-of-function analysis indicated that SGK3 is required for E2-mediated cell survival of MCF-7 breast carcinoma cells. Moreover, overexpression of SGK3 could partially protect MCF-7 cells against apoptosis caused by antiestrogen ICI 182,780. Together, our study defines the molecular mechanism of regulation of SGK3 by estrogen/ER and provides a new link between the PI3K pathway and ER signaling as well as a new estrogen-mediated cell survival mechanism mediated by SGK3 in breast cancer cells.

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Malik, Nazma, Thomas Macartney, Annika Hornberger, Karen E. Anderson, Hannah Tovell, Alan R. Prescott, and Dario R. Alessi. "Mechanism of activation of SGK3 by growth factors via the Class 1 and Class 3 PI3Ks." Biochemical Journal 475, no. 1 (January 2, 2018): 117–35. http://dx.doi.org/10.1042/bcj20170650.

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Derailment of the PI3K-AGC protein kinase signalling network contributes to many human diseases including cancer. Recent work has revealed that the poorly studied AGC kinase family member, SGK3, promotes resistance to cancer therapies that target the Class 1 PI3K pathway, by substituting for loss of Akt kinase activity. SGK3 is recruited and activated at endosomes, by virtue of its phox homology domain binding to PtdIns(3)P. Here, we demonstrate that endogenous SGK3 is rapidly activated by growth factors such as IGF1, through pathways involving both Class 1 and Class 3 PI3Ks. We provide evidence that IGF1 enhances endosomal PtdIns(3)P levels via a pathway involving the UV-RAG complex of hVPS34 Class 3 PI3K. Our data point towards IGF1-induced activation of Class 1 PI3K stimulating SGK3 through enhanced production of PtdIns(3)P resulting from the dephosphorylation of PtdIns(3,4,5)P3. Our findings are also consistent with activation of Class 1 PI3K promoting mTORC2 phosphorylation of SGK3 and with oncogenic Ras-activating SGK3 solely through the Class 1 PI3K pathway. Our results highlight the versatility of upstream pathways that activate SGK3 and help explain how SGK3 substitutes for Akt following inhibition of Class 1 PI3K/Akt pathways. They also illustrate robustness of SGK3 activity that can remain active and counteract physiological conditions or stresses where either Class 1 or Class 3 PI3K pathways are inhibited.

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Malik, Nazma, Raja S. Nirujogi, Julien Peltier, Thomas Macartney, Melanie Wightman, Alan R. Prescott, Robert Gourlay, Matthias Trost, Dario R. Alessi, and Athanasios Karapetsas. "Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44." Biochemical Journal 476, no. 20 (October 30, 2019): 3081–107. http://dx.doi.org/10.1042/bcj20190608.

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Abstract The serum- and glucocorticoid-regulated kinase (SGK) isoforms contribute resistance to cancer therapies targeting the PI3K pathway. SGKs are homologous to Akt and these kinases display overlapping specificity and phosphorylate several substrates at the same residues, such as TSC2 to promote tumor growth by switching on the mTORC1 pathway. The SGK3 isoform is up-regulated in breast cancer cells treated with PI3K or Akt inhibitors and recruited and activated at endosomes, through its phox homology domain binding to PtdIns(3)P. We undertook genetic and pharmacological phosphoproteomic screens to uncover novel SGK3 substrates. We identified 40 potential novel SGK3 substrates, including four endosomal proteins STX7 (Ser126) and STX12 (Ser139), RFIP4 (Ser527) and WDR44 (Ser346) that were efficiently phosphorylated in vitro by SGK3 at the sites identified in vivo, but poorly by Akt. We demonstrate that these substrates are inefficiently phosphorylated by Akt as they possess an n + 1 residue from the phosphorylation site that is unfavorable for Akt phosphorylation. Phos-tag analysis revealed that stimulation of HEK293 cells with IGF1 to activate SGK3, promoted phosphorylation of a significant fraction of endogenous STX7 and STX12, in a manner that was blocked by knock-out of SGK3 or treatment with a pan SGK inhibitor (14H). SGK3 phosphorylation of STX12 enhanced interaction with the VAMP4/VTI1A/STX6 containing the SNARE complex and promoted plasma membrane localization. Our data reveal novel substrates for SGK3 and suggest a mechanism by which STX7 and STX12 SNARE complexes are regulated by SGK3. They reveal new biomarkers for monitoring SGK3 pathway activity.

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Ahmed, Musaab, Myriam Fezai, Nestor L. Uzcategui, Zohreh Hosseinzadeh, and Florian Lang. "SGK3 Sensitivity of Voltage Gated K+ Channel Kv1.5 (KCNA5)." Cellular Physiology and Biochemistry 38, no. 1 (2016): 359–67. http://dx.doi.org/10.1159/000438636.

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Background: The serum & glucocorticoid inducible kinase isoform SGK3 is a powerful regulator of several transporters, ion channels and the Na+/K+ ATPase. Targets of SGK3 include the ubiquitin ligase Nedd4-2, which is in turn a known regulator of the voltage gated K+ channel Kv1.5 (KCNA5). The present study thus explored whether SGK3 modifies the activity of the voltage gated K+ channel KCNA5, which participates in the regulation of diverse functions including atrial cardiac action potential, activity of vascular smooth muscle cells, insulin release and tumour cell proliferation. Methods: cRNA encoding KCNA5 was injected into Xenopus oocytes with and without additional injection of cRNA encoding wild-type SGK3, constitutively active S419DSGK3, inactive K191NSGK3 and/or wild type Nedd4-2. Voltage gated K+ channel activity was quantified utilizing dual electrode voltage clamp. Results: Voltage gated current in KCNA5 expressing Xenopus oocytes was significantly enhanced by wild-type SGK3 and S419DSGK3, but not by K191NSGK3. SGK3 was effective in the presence of ouabain (1 mM) and thus did not require Na+/K+ ATPase activity. Coexpression of Nedd4-2 decreased the voltage gated current in KCNA5 expressing Xenopus oocytes, an effect largely reversed by additional coexpression of SGK3. Conclusion: SGK3 is a positive regulator of KCNA5, which is at least partially effective by abrogating the effect of Nedd4-2.

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Wang, Yuanzhong, Dujin Zhou, Sheryl Phung, Charles Warden, Rumana Rashid, Nymph Chan, and Shiuan Chen. "SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis." Proceedings of the National Academy of Sciences 114, no. 8 (February 7, 2017): E1500—E1508. http://dx.doi.org/10.1073/pnas.1612991114.

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Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum- and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.

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Ranzuglia, Valentina, Ilaria Lorenzon, Ilenia Pellarin, Maura Sonego, Alessandra Dall’Acqua, Sara D’Andrea, Sara Lovisa, et al. "Serum- and glucocorticoid- inducible kinase 2, SGK2, is a novel autophagy regulator and modulates platinum drugs response in cancer cells." Oncogene 39, no. 40 (August 27, 2020): 6370–86. http://dx.doi.org/10.1038/s41388-020-01433-6.

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Abstract For many tumor types chemotherapy still represents the therapy of choice and many standard treatments are based on the use of platinum (PT) drugs. However, de novo or acquired resistance to platinum is frequent and leads to disease progression. In Epithelial Ovarian Cancer (EOC) patients, PT-resistant recurrences are very common and improving the response to treatment still represents an unmet clinical need. To identify new modulators of PT-sensitivity, we performed a loss-of-function screening targeting 680 genes potentially involved in the response of EOC cells to platinum. We found that SGK2 (Serum-and Glucocorticoid-inducible kinase 2) plays a key role in PT-response. We show here that EOC cells relay on the induction of autophagy to escape PT-induced death and that SGK2 inhibition increases PT sensitivity inducing a block in the autophagy cascade due to the impairment of lysosomal acidification. Mechanistically we demonstrate that SGK2 controls autophagy in a kinase-dependent manner by binding and inhibiting the V-ATPase proton pump. Accordingly, SGK2 phosphorylates the subunit V1H (ATP6V1H) of V-ATPase and silencing or chemical inhibition of SGK2, affects the normal autophagic flux and sensitizes EOC cells to platinum. Hence, we identified a new pathway that links autophagy to the survival of cancer cells under platinum treatment in which the druggable kinase SGK2 plays a central role. Our data suggest that blocking autophagy via SGK2 inhibition could represent a novel therapeutic strategy to improve patients’ response to platinum.

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McCormick, James A., Yuxi Feng, Kevin Dawson, Martin J. Behne, Benjamin Yu, Jian Wang, Amanda W. Wyatt, et al. "Targeted Disruption of the Protein Kinase SGK3/CISK Impairs Postnatal Hair Follicle Development." Molecular Biology of the Cell 15, no. 9 (September 2004): 4278–88. http://dx.doi.org/10.1091/mbc.e04-01-0027.

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Members of the serum- and glucocorticoid-regulated kinase (SGK) family are important mediators of growth factor and hormone signaling that, like their close relatives in the Akt family, are regulated by lipid products of phosphatidylinositol-3-kinase. SGK3 has been implicated in the control of cell survival and regulation of ion channel activity in cultured cells. To begin to dissect the in vivo functions of SGK3, we generated and characterized Sgk3 null mice. These mice are viable and fertile, and in contrast to mice lacking SGK1 or Akt2, respectively, display normal sodium handling and glucose tolerance. However, although normal at birth, by postpartum day 4 they have begun to display an unexpected defect in hair follicle morphogenesis. The abnormality in hair follicle development is preceded by a defect in proliferation and nuclear accumulation of β-catenin in hair bulb keratinocytes. Furthermore, in cultured keratinocytes, heterologous expression of SGK3 potently modulates activation of β-catenin/Lef-1–mediated gene transcription. These data establish a role for SGK3 in normal postnatal hair follicle development, possibly involving effects on β-catenin/Lef-1–mediated gene transcription.

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Alonso, Laura, Hitoshi Okada, Hilda Amalia Pasolli, Andrew Wakeham, Annick Itie You-Ten, Tak W. Mak, and Elaine Fuchs. "Sgk3 links growth factor signaling to maintenance of progenitor cells in the hair follicle." Journal of Cell Biology 170, no. 4 (August 15, 2005): 559–70. http://dx.doi.org/10.1083/jcb.200504131.

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Tyrosine kinase growth factor receptor signaling influences proliferation, survival, and apoptosis. Hair follicles undergo cycles of proliferation and apoptotic regression, offering an excellent paradigm to study how this transition is governed. Several factors are known to affect the hair cycle, but it remains a mystery whether Akt kinases that are downstream of growth factor signaling impact this equilibrium. We now show that an Akt relative, Sgk (serum and glucocorticoid responsive kinase) 3, plays a critical role in this process. Hair follicles of mice lacking Sgk3 fail to mature normally. Proliferation is reduced, apoptosis is increased, and follicles prematurely regress. Maintenance of the pool of transiently amplifying matrix cells is impaired. Intriguingly, loss of Sgk3 resembles the gain of function of epidermal growth factor signaling. Using cultured primary keratinocytes, we find that Sgk3 functions by negatively regulating phosphatidylinositol 3 kinase signaling. Our results reveal a novel and important function for Sgk3 in controlling life and death in the hair follicle.

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Minchenko, D. O., O. O. Riabovol, D. O. Tsymbal, O. O. Ratushna, and O. H. Minchenko. "Inhibition of IRE1 signaling affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells." Endocrine Regulations 50, no. 3 (July 1, 2016): 127–36. http://dx.doi.org/10.1515/enr-2016-0014.

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Abstract Objective. The aim of the present investigation was to examine the effect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoding glucocorticoid receptor (NR3C1) and some related proteins (SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, NNT) and their hypoxic regulation in U87 glioma cells for evaluation of their possible significance in the control of the glioma growth. Methods. The expression of NR3C1,SGK1,SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by quantitative polymerase chain reaction. Results. Inhibition of IRE1 signaling enzyme function up-regulates the expression of NR3C1, SGK1, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells in comparison with the control glioma cells, with more significant changes for NR3C1, SGK1, and NNT genes. At the same time, the expression of SGK3 gene is strongly down-regulated in glioma cells upon inhibition of IRE1. We have also shown that hypoxia increases the expression of NR3C1, SGK1, NCOA2, ARHGAP35, and NNT genes but decreases SGK3 and NCOA1 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in U87 glioma cells enhances the eff ect of hypoxia on the expression of SGK1, SGK3, and NNT genes, but decreases the sensitivity of NR3C1 gene to hypoxic condition. Furthermore, the expression of NCOA1 gene is resistant to hypoxia in control glioma cells, but NCOA2 and ARHGAP35 genes are resistant to this condition in glioma cells without functional activity of IRE1 signaling enzyme. Conclusions. Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function affects the expression of NR3C1, SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells in gene specific manner and that all these genes are regulated by hypoxia preferentially through IRE1 signaling pathway of the endoplasmic reticulum stress.

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Tovell, Hannah, Andrea Testa, Houjiang Zhou, Natalia Shpiro, Claire Crafter, Alessio Ciulli, and Dario R. Alessi. "Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader." ACS Chemical Biology 14, no. 9 (August 28, 2019): 2024–34. http://dx.doi.org/10.1021/acschembio.9b00505.

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Yao, Li-Jun, James A. McCormick, Jian Wang, Katherine Y. Yang, Atif Kidwai, Gian Luca Colussi, Krishna M. Boini, et al. "Novel Role for SGK3 in Glucose Homeostasis Revealed in SGK3/Akt2 Double-Null Mice." Molecular Endocrinology 25, no. 12 (December 1, 2011): 2106–18. http://dx.doi.org/10.1210/me.2010-0329.

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Mouton, Véronique, Louise Toussaint, Didier Vertommen, Marie-Agnès Gueuning, Liliane Maisin, Xavier Havaux, Cossette Sanchez-Canedo, et al. "Heart 6-phosphofructo-2-kinase activation by insulin requires PKB (protein kinase B), but not SGK3 (serum- and glucocorticoid-induced protein kinase 3)." Biochemical Journal 431, no. 2 (September 28, 2010): 267–75. http://dx.doi.org/10.1042/bj20101089.

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On the basis of transfection experiments using a dominant-negative approach, our previous studies suggested that PKB (protein kinase B) was not involved in heart PFK-2 (6-phosphofructo2-kinase) activation by insulin. Therefore we first tested whether SGK3 (serum- and glucocorticoid-induced protein kinase 3) might be involved in this effect. Treatment of recombinant heart PFK-2 with [γ-32P]ATP and SGK3 in vitro led to PFK-2 activation and phosphorylation at Ser466 and Ser483. However, in HEK-293T cells [HEK (human embryonic kidney)-293 cells expressing the large T-antigen of SV40 (simian virus 40)] co-transfected with SGK3 siRNA (small interfering RNA) and heart PFK-2, insulin-induced heart PFK-2 activation was unaffected. The involvement of PKB in heart PFK-2 activation by insulin was re-evaluated using different models: (i) hearts from transgenic mice with a muscle/heart-specific mutation in the PDK1 (phosphoinositide-dependent protein kinase 1)-substrate-docking site injected with insulin; (ii) hearts from PKBβ-deficient mice injected with insulin; (iii) freshly isolated rat cardiomyocytes and perfused hearts treated with the selective Akti-1/2 PKB inhibitor prior to insulin treatment; and (iv) HEK-293T cells co-transfected with heart PFK-2, and PKBα/β siRNA or PKBα siRNA, incubated with insulin. Together, the results indicated that SGK3 is not required for insulin-induced PFK-2 activation and that this effect is likely mediated by PKBα.

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Riabovol, Olena O., Dariia O. Tsymbal, Dmytro O. Minchenko, Kateryna M. Lebid-Biletska, Myroslava Y. Sliusar, Olha V. Rudnytska, and Oleksandr H. Minchenko. "Effect of glucose deprivation on the expression of genes encoding glucocorticoid receptor and some related factors in ERN1-knockdown U87 glioma cells." Endocrine Regulations 53, no. 4 (October 1, 2019): 237–49. http://dx.doi.org/10.2478/enr-2019-0024.

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AbstractObjective. The aim of the present study was to examine the effect of glucose deprivation on the expression of genes encoded glucocorticoid receptor (NR3C1) and some related proteins (NR3C2, AHR, NRIP1, NNT, ARHGAP35, SGK1, and SGK3) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1/inositol requiring enzyme 1) for evaluation of their possible significance in the control of glioma growth through endoplasmic reticulum stress signaling mediated by IRE1 and glucose deprivation.Methods. The expression of NR3C1, NR3C2, AHR, NRIP1, NNT, ARHGAP35, SGK1, and SGK3 genes in U87 glioma cells transfected by empty vector pcDNA3.1 (control cells) and cells without ERN1 signaling enzyme function (transfected by dnERN1) under glucose deprivation was studied by real time quantitative polymerase chain reaction.Results. It was shown that the expression level of NR3C2, AHR, SGK1, SGK3, and NNT genes was up-regulated in control U87 glioma cells under glucose deprivation condition in comparison with the control cells growing with glucose. At the same time, the expression of NRIP1 gene is down-regulated in these glioma cells under glucose deprivation, but NR3C1 and ARHGAP35 genes was resistant to this experimental condition. We also showed that inhibition of ERN1 signaling enzyme function significantly modified the response of most studied gene expressions to glucose deprivation condition. Thus, effect of glucose deprivation on the expression level of NR3C2, AHR, and SGK1 genes was significantly stronger in ERN1 knockdown U87 glioma cells since the expression of NNT gene was resistant to glucose deprivation condition. Moreover, the inhibition of ERN1 enzymatic activities in U87 glioma cells led to up-regulation of ARHGAP35 gene expression and significant down-regulation of the expression of SGK3 gene in response to glucose deprivation condition.Conclusions. Results of this study demonstrated that glucose deprivation did not change the expression level of NR3C1 gene but it significantly affected the expression of NR3C2, AHR, NRIP, SGK1, SGK3, and NNT genes in vector-transfected U87 glioma cells in gene specific manner and possibly contributed to the control of glioma growth since the expression of most studied genes in glucose deprivation condition was significantly dependent on the functional activity of IRE1 signaling enzyme.

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Jian, Yanping, Zongbin Song, Zhuofeng Ding, Jian Wang, Ruike Wang, and Xinran Hou. "Upregulation of Spinal miR-155-5p Contributes to Mechanical Hyperalgesia by Promoting Inflammatory Activation of Microglia in Bone Cancer Pain Rats." Life 12, no. 9 (August 30, 2022): 1349. http://dx.doi.org/10.3390/life12091349.

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Bone cancer pain (BCP) seriously deteriorates the life quality of patients, but its underlying mechanism is still unclear. Spinal microRNAs might contribute to the development of BCP and the role of microglial activation is controversial. In this study, we established a BCP model by injecting Walker 256 breast carcinoma cells into the tibial intramedullary cavity of rats and significant hyperalgesia was observed in the BCP rats. The lumbar spinal cords were harvested to perform RNA sequencing (RNA-seq), and 31 differentially expressed miRNAs (26 upregulated and 5 downregulated) were identified in the BCP rats. Among them, miR-155-5p was significantly upregulated in the BCP rats. Spinal microglial activation was observed during BCP development. miR-155-5p could be expressed in spinal microglia and was significantly upregulated in microglia treated with lipopolysaccharide (LPS) in vitro. Serum/glucocorticoid regulated kinase family member 3 (Sgk3) was predicted to be the possible downstream target of miR-155-5p and this was confirmed using a dual-luciferase reporter assay in vitro. The inhibition of miR-155-5p restored Sgk3-expression-attenuated microglial activation and alleviated hyperalgesia in the BCP rats. In conclusion, spinal miR-155-5p/Sgk3/microglial activation might play an important role in BCP pathogenesis.

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HOU, MINZHI, YINGRONG LAI, SHANYANG HE, WEILING HE, HONGWEI SHEN, and ZUNFU KE. "SGK3 (CISK) may induce tumor angiogenesis (Hypothesis)." Oncology Letters 10, no. 1 (May 6, 2015): 23–26. http://dx.doi.org/10.3892/ol.2015.3182.

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Bago, Ruzica, Nazma Malik, Michael J. Munson, Alan R. Prescott, Paul Davies, Eeva Sommer, Natalia Shpiro, et al. "Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide 3-kinase." Biochemical Journal 463, no. 3 (October 10, 2014): 413–27. http://dx.doi.org/10.1042/bj20140889.

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We characterize VPS34-IN, a potent and selective inhibitor of class III Vps34 PI3K. Using VPS34-IN1, we demonstrate that PtdIns(3)P, produced by Vps34 controls phosphorylation and activity of the SGK3 protein kinase.

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Cebeci, Ayşe Nurcan, Minjing Zou, Huda A. BinEssa, Ali S. Alzahrani, Roua A. Al-Rijjal, Anwar F. Al-Enezi, Futwan A. Al-Mohanna, Etienne Cavalier, Brian F. Meyer, and Yufei Shi. "Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets." Journal of Clinical Endocrinology & Metabolism 105, no. 6 (December 10, 2019): 1840–50. http://dx.doi.org/10.1210/clinem/dgz260.

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Abstract Context Hypophosphatemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3. Objective A large kindred with 5 HR patients was recruited with dominant inheritance. The study was undertaken to investigate underlying genetic defects in HR patients. Design Patients and their family members were initially analyzed for PHEX and FGF23 mutations using polymerase chain reaction sequencing and copy number analysis. Exome sequencing was subsequently performed to identify novel candidate genes. Results PHEX and FGF23 mutations were not detected in the patients. No copy number variation was observed in the genome using CytoScan HD array analysis. Mutations in DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 were also not found by exome sequencing. A novel c.979–96 T>A mutation in the SGK3 gene was found to be strictly segregated in a heterozygous pattern in patients and was not present in normal family members. The mutation is located 1 bp downstream of a highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids, which is part of the protein kinase domain and contains a Thr-320 phosphorylation site that is required for its activation. Protein tertiary structure modelling showed significant structural change in the protein kinase domain following the deletion. Conclusions The c.979–96 T>A splice mutation in the SGK3 gene causes exon 13 skipping and deletion of 29 amino acids in the protein kinase domain. The SGK3 mutation may cause autosomal dominant HR.

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Croucher, David R., Falko Hochgräfe, Luxi Zhang, Ling Liu, Ruth J. Lyons, Danny Rickwood, Carole M. Tactacan, et al. "Involvement of Lyn and the Atypical Kinase SgK269/PEAK1 in a Basal Breast Cancer Signaling Pathway." Cancer Research 73, no. 6 (February 1, 2013): 1969–80. http://dx.doi.org/10.1158/0008-5472.can-12-1472.

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Du, William W., Jindong Xu, Weining Yang, Nan Wu, Feiya Li, Le Zhou, Sheng Wang, et al. "A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling." Circulation Research 129, no. 5 (August 20, 2021): 568–82. http://dx.doi.org/10.1161/circresaha.120.318364.

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Background: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrhythmia and progressive heart failure. The underlying mechanisms remain unclear. We performed high-throughput RNA sequencing to analyze circular RNA profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA–derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 (inhibitor of growth protein 4) and C8orf44-SGK3 (serum and glucocorticoid-inducible kinase-3) promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn-transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared with WT (wild type) mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload–induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.

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Pan, Jiangang, Xin Lv, Decai Jin, Zhihui Bai, Hongyan Qi, Hongxun Zhang, and Guoqiang Zhuang. "Developmental stage has a greater effect than Cry1Ac expression in transgenic cotton on the phyllosphere mycobiome." Canadian Journal of Microbiology 65, no. 2 (February 2019): 116–25. http://dx.doi.org/10.1139/cjm-2018-0309.

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Transgenic Bt cotton is widely cultivated, yet its impact on the phyllosphere mycobiome is poorly understood. Hence, the objective of this study was to investigate the effects resulting from the planting of Bt cotton on fungal diversity composition. The α diversity for the Bt cotton line SGK321 was lower than that of control plants at the budding stage and the blossoming and boll-forming stage, while an obvious increase in diversity for Bt cotton XP188 was observed at the same stage. The Cry1Ac levels were higher at the seedling stage than at the budding stage and the blossoming and boll-forming stage. There was no direct relationship between the expression of the Bt protein and variation in the fungal community for Bt cotton. However, PCoA and PCA results indicated that community structure differed among developmental stages. These results indicated that developmental stage rather than Cry1Ac expression was the key factor shaping the phyllosphere mycobiome in transgenic cotton.

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Trepiccione, Francesco, and Giovambattista Capasso. "SGK3: a novel regulator of renal phosphate transport?" Kidney International 80, no. 1 (July 2011): 13–15. http://dx.doi.org/10.1038/ki.2011.60.

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Zhou, Nannan, Bo Ding, Michele Agler, Mark Cockett, and Fiona McPhee. "Lethality of PAK3 and SGK2 shRNAs to Human Papillomavirus Positive Cervical Cancer Cells Is Independent of PAK3 and SGK2 Knockdown." PLOS ONE 10, no. 1 (January 23, 2015): e0117357. http://dx.doi.org/10.1371/journal.pone.0117357.

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Yang, Xuanyi, Yu Cao, Cen Yan, Yuejie Zhang, Yuan Dong, and Yingmei Feng. "S-09-5: EPIDEMIOLOGY AND CARDIOMETABOLIC DISORDERS - UPDATE OF SGKT2-IS RCT META-ANALYSIS." Journal of Hypertension 41, Suppl 1 (January 2023): e30. http://dx.doi.org/10.1097/01.hjh.0000912984.49909.25.

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Schmid, Evi, Madhuri Bhandaru, Meerim K. Nurbaeva, Wenting Yang, Kalina Szteyn, Antonella Russo, Christina Leibrock, et al. "SGK3 Regulates Ca2+Entry and Migration of Dendritic Cells." Cellular Physiology and Biochemistry 30, no. 6 (2012): 1423–35. http://dx.doi.org/10.1159/000343330.

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Gasser, Jessica A., Hiroyuki Inuzuka, Alan W. Lau, Wenyi Wei, Rameen Beroukhim, and Alex Toker. "SGK3 Mediates INPP4B-Dependent PI3K Signaling in Breast Cancer." Molecular Cell 56, no. 4 (November 2014): 595–607. http://dx.doi.org/10.1016/j.molcel.2014.09.023.

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Sandu, Ciprian, Rexhep Rexhepaj, Florian Grahammer, James A. McCormick, Guido Henke, Monica Palmada, Srinivas Nammi, et al. "Decreased intestinal glucose transport in the sgk3-knockout mouse." Pflügers Archiv - European Journal of Physiology 451, no. 3 (June 22, 2005): 437–44. http://dx.doi.org/10.1007/s00424-005-1474-7.

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Pokorny, Daniel, Linda Truebestein, Kaelin D. Fleming, John E. Burke, and Thomas A. Leonard. "In vitro reconstitution of Sgk3 activation by phosphatidylinositol 3-phosphate." Journal of Biological Chemistry 297, no. 2 (August 2021): 100919. http://dx.doi.org/10.1016/j.jbc.2021.100919.

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Xu, Jun, Ma Wan, Quanyuan He, Roland L. Bassett, Xiaoyong Fu, Albert C. Chen, Fengtao Shi, et al. "SGK3 is associated with estrogen receptor expression in breast cancer." Breast Cancer Research and Treatment 134, no. 2 (May 11, 2012): 531–41. http://dx.doi.org/10.1007/s10549-012-2081-x.

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Liu, Huailei, Chenguang Li, Chen Shen, Fei Yin, Kaikai Wang, Yaohua Liu, Bingjie Zheng, et al. "MiR-212-3p inhibits glioblastoma cell proliferation by targeting SGK3." Journal of Neuro-Oncology 122, no. 3 (February 27, 2015): 431–39. http://dx.doi.org/10.1007/s11060-015-1736-y.

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Journal articles on the topic 'SgK223'

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