Identification of the kinase STK25 as an upstream activator of LATS signaling

Lim, Sanghee; Hermance, Nicole; Mudianto, Tenny; Mustaly, Hatim M.; Mauricio, Ian Paolo Morelos; Vittoria, Marc A.; Quinton, Ryan J.; Howell, Brian W.; Cornils, Hauke; Manning, Amity L.; Ganem, Neil J.

doi:10.1038/s41467-019-09597-w

Cited by 45 publications

(52 citation statements)

References 53 publications

(78 reference statements)

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“…Increasing evidence has identified that the aberrant expression of tumor-related kinases is closely connected to the progression, therapeutic resistance or recurrence of various cancers [42][43][44][45]. The polo-like kinases (PLKs) are among these protein kinases that control multiple complex process of centriole duplication [46].…”

Section: Discussionmentioning

confidence: 99%

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of notch signaling

Wahafu

et al. 2020

J Exp Clin Cancer Res

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Background Glioblastoma (GBM) is a lethal type of primary brain tumor with a median survival less than 15 months. Despite the recent improvements of comprehensive strategies, the outcomes for GBM patients remain dismal. Accumulating evidence indicates that rapid acquired chemoresistance is the major cause of GBM recurrence thus leads to worse clinical outcomes. Therefore, developing novel biomarkers and therapeutic targets for chemoresistant GBM is crucial for long-term cures. Methods Transcriptomic profiles of glioblastoma were downloaded from gene expression omnibus (GEO) and TCGA database. Differentially expressed genes were analyzed and candidate gene PLK2 was selected for subsequent validation. Clinical samples and corresponding data were collected from our center and measured using immunohistochemistry analysis. Lentiviral transduction and in vivo xenograft transplantation were used to validate the bioinformatic findings. GSEA analyses were conducted to identify potential signaling pathways related to PLK2 expression and further confirmed by in vitro mechanistic assays. Results In this study, we identified PLK2 as an extremely suppressed kinase-encoding gene in GBM samples, particularly in therapy resistant GBM. Additionally, reduced PLK2 expression implied poor prognosis and TMZ resistance in GBM patients. Functionally, up-regulated PLK2 attenuated cell proliferation, migration, invasion, and tumorigenesis of GBM cells. Besides, exogenous overexpression of PLK2 reduced acquired TMZ resistance of GBM cells. Furthermore, bioinformatics analysis indicated that PLK2 was negatively correlated with Notch signaling pathway in GBM. Mechanically, loss of PLK2 activated Notch pathway through negative transcriptional regulation of HES1 and degradation of Notch1. Conclusion Loss of PLK2 enhances aggressive biological behavior of GBM through activation of Notch signaling, indicating that PLK2 could be a prognostic biomarker and potential therapeutic target for chemoresistant GBM.

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Section: Discussionmentioning

confidence: 99%

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of notch signaling

Wahafu

et al. 2020

J Exp Clin Cancer Res

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“…These kinases phosphorylate LATS1/2 at a site called the hydrophobic motif (HM), which then stimulates the kinase to autophosphorylate at the activation loop (AL) site to become fully active. STK25 was recently shown to directly phosphorylate LATS1/2 at the AL site to stimulate its activity when F-actin is disrupted (54). What remains unclear is whether the LATS1/2 upstream kinases are themselves regulated by F-actin or simply required for other mechanisms that promote LATS1/2 activation by loss of F-actin ( Fig.…”

Section: Actin Cytoskeletonmentioning

confidence: 99%

Control of cellular responses to mechanical cues through YAP/TAZ regulation

Dasgupta

McCollum

2019

Journal of Biological Chemistry

247

190

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To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.

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“…Tao kinase (TAOK) phosphorylates and activates MST1 and LATS1/2 (23), and several mitogen-activated protein kinase kinase kinase kinase (MAP4K) family members directly phosphorylate and activate LATS1/2 (24,25). A recent study has also shown that STK25 phosphorylates LATS1/2 and contribute to the activation of LATS1/2 in response to contact inhibition and cell detachment (26). In addition, tumor suppressor Neurofibromin 2 (NF2) is a critical activator of LATS1/2 (27).…”

Section: Regulation Of Yap/tazmentioning

confidence: 99%

A Potential Role of YAP/TAZ in the Interplay Between Metastasis and Metabolic Alterations

Yamaguchi

Taouk

2020

Front. Oncol.

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Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) are the downstream effectors of the Hippo signaling pathway that play a crucial role in various aspects of cancer progression including metastasis. Metastasis is the multistep process of disseminating cancer cells in a body and responsible for the majority of cancer-related death. Emerging evidence has shown that cancer cells reprogram their metabolism to gain proliferation, invasion, migration, and anti-apoptotic abilities and adapt to various environment during metastasis. Moreover, it has increasingly been recognized that YAP/TAZ regulates cellular metabolism that is associated with the phenotypic changes, and recent studies suggest that the YAP/TAZ-mediated metabolic alterations contribute to metastasis. In this review, we will introduce the latest knowledge of YAP/TAZ regulation and function in cancer metastasis and metabolism, and discuss possible links between the YAP/TAZ-mediated metabolic reprogramming and metastasis.

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Identification of the kinase STK25 as an upstream activator of LATS signaling

Cited by 45 publications

References 53 publications

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of notch signaling

Loss of PLK2 induces acquired resistance to temozolomide in GBM via activation of notch signaling

Control of cellular responses to mechanical cues through YAP/TAZ regulation

A Potential Role of YAP/TAZ in the Interplay Between Metastasis and Metabolic Alterations

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