The TLK1/Nek1 axis contributes to mitochondrial integrity and apoptosis prevention via phosphorylation of VDAC1

Singh, Vibha; Khalil, Md Imtiaz; Benedetti, Arrigo De

doi:10.1080/15384101.2019.1711317

Cited by 28 publications

(34 citation statements)

References 25 publications

(54 reference statements)

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“…Resistance to androgen deprivation therapy (ADT) promotes androgen-independent growth and proliferation of PCa cells, which requires efficient DNA damage response (DDR) and repair mechanisms, activation of compensatory signaling pathways, transcription factors, and co-factors to drive castration resistance. Findings from our lab and others suggest that ADT activates the TLK1-NEK1 signaling pathway that promotes PCa progression by activating the DDR [11,24]. Hyper-activation of NEK1 may also lengthen G2/M checkpoints, which provides the cells sufficient time to repair their damaged DNA after ADT or radiation therapy [7,58].…”

Section: Discussionmentioning

confidence: 77%

“…During studies aimed at elucidating the process of ADT adaptation of AS PCa cell (initially in LNCaP), which proceeds through a process of activating the DDR and increased activity of the kinases TLK1B and NEK1 [11,24,25], we made the observation that overexpression of wt-NEK1, but not the hypoactive NEK1-T141A variant that cannot be activated by TLK, resulted in a rapid adaptation to bicalutamide and formation of AI colonies. From a review of the literature on the process of AI conversion of LNCaP and other studies of CRPC progression, we suspected the involvement of Hippo pathway deregulation and, in particular, YAP-driven gene expression (for a recent review, see [43]).…”

Section: Discussionmentioning

confidence: 99%

“…Genomic instability is also manifested in NEK1 +/− mice, which later in life develop lymphomas with a higher incidence than wild type littermates [9]. NEK1 is also known to negatively regulate apoptosis by phosphorylating VDAC1, regulating the closure of the anion channel of the mitochondrial membrane, which promotes survival of renal cell carcinoma [10][11][12]. Loss of function mutation of NEK1 leads to DNA damage accumulation in the motorneurons that may lead to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) [13,14].…”

Section: Introductionmentioning

confidence: 99%

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NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Khalil

Ghosh

Singh

et al. 2020

Cancers

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Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) and never in mitosis gene A (NIMA)-related kinase 1 (NEK1) in a DNA damage response (DDR)-mediated cell cycle arrest in LNCaP cells treated with bicalutamide, we uncovered that overexpression of wt-NEK1 resulted in a rapid conversion to androgen-independent (AI) growth, analogous to what has been observed when YAP1 is overexpressed. We now report that overexpression of wt-NEK1 results in accumulation of YAP1, suggesting the existence of a TLK1>NEK1>YAP1 axis that leads to adaptation to AI growth. Further, YAP1 is co-immunoprecipitated with NEK1. Importantly, NEK1 was able to phosphorylate YAP1 on six residues in vitro, which we believe are important for stabilization of the protein, possibly by increasing its interaction with transcriptional partners. In fact, knockout (KO) of NEK1 in NT1 PCa cells resulted in a parallel decrease of YAP1 level and reduced expression of typical YAP-regulated target genes. In terms of cancer potential implications, the expression of NEK1 and YAP1 proteins was found to be increased and correlated in several cancers. These include PCa stages according to Gleason score, head and neck squamous cell carcinoma, and glioblastoma, suggesting that this co-regulation is imparted by increased YAP1 stability when NEK1 is overexpressed or activated by TLK1, and not through transcriptional co-expression. We propose that the TLK1>NEK1>YAP1 axis is a key determinant for cancer progression, particularly during the process of androgen-sensitive to -independent conversion during progression to mCRPC.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

Khalil

Ghosh

Singh

et al. 2020

Cancers

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“…NEKs may be assigned to three major functional contexts: centrioles and mitotic spindle functions (NEK2, NEK5, NEK6, NEK7, and NEK9), primary ciliary function (NEK1, NEK4, NEK8, and NEK10), and G2/M phase-associated DDR (NEK1, NEK5, NEK4, NEK6, NEK8, NEK10, and NEK11) [1,2,[4][5][6]. Recently, many publications have been addressing new roles of NEK family members apart from cell-cycle control [3], including regulation of cytosolic proteins [7,8], mitochondrial function and regulation of apoptosis [9][10][11][12], autophagy [13,14], inflammasome response [15,16], and splicing [17,18], apart from their involvement in disease processes [19,20].…”

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confidence: 99%

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

et al. 2021

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Little is known about Nima‐related kinase (NEKs), a widely conserved family of kinases that have key roles in cell‐cycle progression. Nevertheless, it is now clear that multiple NEK family members act in networks, not only to regulate specific events of mitosis, but also to regulate metabolic events independently of the cell cycle. NEK5 was shown to act in centrosome disjunction, caspase‐3 regulation, myogenesis, and mitochondrial respiration. Here, we demonstrate that NEK5 interacts with LonP1, an AAA+ mitochondrial protease implicated in protein quality control and mtDNA remodeling, within the mitochondria and it might be involved in the LonP1‐TFAM signaling module. Moreover, we demonstrate that NEK5 kinase activity is required for maintaining mitochondrial mass and functionality and mtDNA integrity after oxidative damage. Taken together, these results show a new role of NEK5 in the regulation of mitochondrial homeostasis and mtDNA maintenance, possibly due to its interaction with key mitochondrial proteins, such as LonP1.

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“…Consequently, irradiation of fibroblasts with a dominant negative form of Nek1 or transiently depleted Nek1 resulted in spindle defects, abnormal chromosome segregation and prevented G1/S or G2/M phase arrest [12,13]. Furthermore, the TLK1/Nek1 axis mediates a persistent voltage-dependent anion channel 1 phosphorylation and prevents cytochrome C release from mitochondria [14,15] and the execution of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1

Freund

Hehlgans

Martin

et al. 2020

Cells

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NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.

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The TLK1/Nek1 axis contributes to mitochondrial integrity and apoptosis prevention via phosphorylation of VDAC1

Abstract: Benedetti (2020) The TLK1/Nek1 axis contributes to mitochondrial integrity and apoptosis prevention via phosphorylation of VDAC1,

Cited by 28 publications

References 25 publications

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1

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