Serum and glucocorticoid inducible protein kinases (SGKs): a potential target for cancer intervention

Basnet, Rajesh; Gong, Grace Qun; Li, Chenyao; Wang, Mingwei

doi:10.1016/j.apsb.2018.07.001

Cited by 31 publications

(25 citation statements)

References 39 publications

(55 reference statements)

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“…The serum/glucocorticoid-regulated kinase isoforms SGK1, SGK2, and SGK3 belong to a subgroup of the AGC (cAMP-dependent, cGMP-dependent, and protein kinase C) family of protein kinases that play a role in multiple cellular processes including cell growth, proliferation, metabolism, intracellular trafficking and survival [ 141 , 142 , 143 ]. SGK1 and 3 are considered to be ubiquitously expressed, while SGK2 expression is prominent in the liver, kidney, pancreas, and brain [ 144 ].…”

Section: Genetic Aberrations In the Pi3k-akt-mtor Pathway In Prostmentioning

confidence: 99%

“…SGK1 and 3 are considered to be ubiquitously expressed, while SGK2 expression is prominent in the liver, kidney, pancreas, and brain [ 144 ]. SGKs share structural similarities, upstream regulators, substrates and functions with the AKT isoforms (reviewed in [ 142 ]). For instance, all SGKs are phosphorylated and activated by PDK1, and SGK1 is a downstream target of mTORC2 [ 26 , 143 , 145 , 146 , 147 , 148 ] ( Figure 1 ).…”

Section: Genetic Aberrations In the Pi3k-akt-mtor Pathway In Prostmentioning

confidence: 99%

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The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

Shorning

Dass

Smalley

et al. 2020

IJMS

359

251

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Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin (mTOR) pathway is a frequent event in prostate cancer that facilitates tumor formation, disease progression and therapeutic resistance. Recent discoveries indicate that the complex crosstalk between the PI3K-AKT-mTOR pathway and multiple interacting cell signaling cascades can further promote prostate cancer progression and influence the sensitivity of prostate cancer cells to PI3K-AKT-mTOR-targeted therapies being explored in the clinic, as well as standard treatment approaches such as androgen-deprivation therapy (ADT). However, the full extent of the PI3K-AKT-mTOR signaling network during prostate tumorigenesis, invasive progression and disease recurrence remains to be determined. In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.

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Section: Genetic Aberrations In the Pi3k-akt-mtor Pathway In Prostmentioning

confidence: 99%

Section: Genetic Aberrations In the Pi3k-akt-mtor Pathway In Prostmentioning

confidence: 99%

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

Shorning

Dass

Smalley

et al. 2020

IJMS

359

251

View full text Add to dashboard Cite

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“…The SGK family consists of three members: SGK1, SGK2, and SGK3 78 . The SGK family has a three-dimensional structure and sequence similar to those of the protein kinase B (PKB)/AKT family 78,79 . Importantly, a series of experiments using the CRISPR/CAS9 genome editing technique to knock out SGK1, 2, or 3 revealed that SGK3, but not SGK1 or 2, is a critical mediator of ACD (Fig.…”

Section: Psychological Stressmentioning

confidence: 99%

“…SGK3 contains a complete Phox homology (PX) domain 78 , 80 , which contains a phosphoinositide-binding site. Phosphatidylinositol 3-phosphate (PtdIns3P) is the most common lipid that binds to the PX domain, and it is enriched in endosomes and vacuoles; SGK3 binds PtdIns3P and is located mostly in endosomes 79 . PtdIns3P is a product of PI3K and regulates the initiation of autophagy 81 .…”

Section: Introductionmentioning

confidence: 99%

Autophagy as a decisive process for cell death

2020

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Autophagy is an intracellular catabolic pathway in which cellular constituents are engulfed by autophagosomes and degraded upon autophagosome fusion with lysosomes. Autophagy serves as a major cytoprotective process by maintaining cellular homeostasis and recycling cytoplasmic contents. However, emerging evidence suggests that autophagy is a primary mechanism of cell death (autophagic cell death, ACD) and implicates ACD in several aspects of mammalian physiology, including tumor suppression and psychological disorders. However, little is known about the physiological roles and molecular mechanisms of ACD. In this review, we document examples of ACD and discuss recent progress in our understanding of its molecular mechanisms.

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“…In our study, our experimental data corroborate our computational modelling predictions and indicate that, depending on the cellular context, the PI3K/SGK3 axis represents an alternative oncogenic signalling pathway involved in L-plastin activation. Knowing that this PI3K-dependent, AKT-independent signalling axis signi cantly contributes to cancer progression (43), it deserves close attention and SGK inhibitors might be promising therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

L-Plastin Ser5 Phosphorylation is Modulated by the PI3K/SGK Pathway and Promotes Breast Cancer Cell Invasiveness

Machado

Stojevski

Landtsheer

et al. 2020

Preprint

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BackgroundMetastasis is the predominant cause for cancer morbidity and mortality accounting for approximatively 90% of cancer deaths. The actin-bundling protein L-plastin has been proposed as a metastatic marker and phosphorylation on its residue Ser5 is known to increase its actin-bundling activity. We recently showed that activation of the ERK/MAPK signalling pathway leads to L-plastin Ser5 phosphorylation and that the downstream kinases RSK1 and RSK2 are able to directly phosphorylate Ser5. Here we investigate the involvement of the PI3K pathway in L-plastin Ser5 phosphorylation and the functional effect of this phosphorylation event in breast cancer cells. MethodsTo unravel the signal transduction network upstream of L-plastin Ser5 phosphorylation, we performed computational modelling based on immunoblot analysis data, followed by experimental validation through inhibition/overexpression studies and in vitro kinase assays. To assess the functional impact of L-plastin expression/Ser5 phosphorylation in breast cancer cells, we either silenced L-plastin in cell lines initially expressing endogenous L-plastin or neoexpressed L-plastin wild type and phosphovariants in cell lines devoid of endogenous L-plastin. The established cell lines were used for cell biology experiments and confocal microscopy analysis.ResultsOur modelling approach revealed that, in addition to the ERK/MAPK pathway and depending on the cellular context, the PI3K pathway contributes to L-plastin Ser5 phosphorylation through its downstream kinase SGK3. The results of the transwell invasion/migration assays showed that shRNA-mediated knockdown of L-plastin in BT-20 or HCC38 cells significantly reduced cell invasion, whereas stable expression of the phosphomimetic L-plastin Ser5Glu variant led to increased migration and invasion of BT-549 and MDA-MB-231 cells. Finally, confocal image analysis combined with zymography experiments and gelatin degradation assays provided evidence that L-plastin Ser5 phosphorylation promotes L-plastin recruitment to invadopodia, MMP-9 activity and concomitant extracellular matrix degradation. ConclusionAltogether, our results demonstrate that L-plastin Ser5 phosphorylation increases breast cancer cell invasiveness. Being a downstream molecule of both ERK/MAPK and PI3K/SGK pathways, L-plastin is proposed here as a potential target for therapeutic approaches that are aimed at blocking dysregulated signalling outcome of both pathways and, thus, at impairing cancer cell invasion and metastasis formation.

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Serum and glucocorticoid inducible protein kinases (SGKs): a potential target for cancer intervention

Cited by 31 publications

References 39 publications

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

Autophagy as a decisive process for cell death

L-Plastin Ser5 Phosphorylation is Modulated by the PI3K/SGK Pathway and Promotes Breast Cancer Cell Invasiveness

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