PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity

Matsuda, Shinya; Kawamoto, Kohei; Miyamoto, K.; Tsuji, Akihiko; Yuasa, Keizo

doi:10.1038/srep45545

Cited by 27 publications

(14 citation statements)

References 56 publications

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“…Besides, transplanted MSCs-induced chemokines and adhesion factors are also involved in the process of bone regeneration [37]. Moreover, prior research found that the activated FAK via phosphorylation could aggregate with integrins at focal adhesion complexes in response to fluid shear stress, mechanical stimulus and cell adhesion [38,39]. FAK has been identified as an important mediator in signal transduction during cell proliferation, migration and differentiation of osteoblasts [40].…”

Section: Discussionmentioning

confidence: 99%

FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells

Zheng

Sun

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Objective: Focal adhesion kinase (FAK) has critical functions in proliferation and differentiation of many cell types, however, the role of FAK on BMP9-induced osteogenic differentiation in SMSCs has not been characted. The purpose of current study is to explore the mechanism of FAK on the BMP9induced osteogenesis of SMSCs in vitro and in vivo. Methods: The optimal dose of BMP9 was determined by incubation in different BMP9 concentrations, then cells were transfected with siRNA-induced FAK knockdown in BMP9-induced osteogenesis. Cell proliferation, migration, the osteogenic capacity, and the underlying mechanism were further detected in vitro. Imaging and pathological examination were conducted to observe the bone formation in vivo. Results: Our findings suggested that BMP9 could obviously promote FAK phosphorylation in osteogenic conditions. In contrast, FAK knockdown significantly decreased the cell proliferation, migration, the osteogenic capacity of SMSCs. To be specific, FAK knockdown could markedly inhibit the Wnt and MAPK signal pathway of SMSCs induced by BMP9. Besides, FAK knockdown could also effectively inhibit BMP-9-induced bone formation in vivo. Conclusion: FAK plays a pivotal role in promoting BMP9-induced osteogenesis of SMSCs, which is probably via activating Wnt and MAPK pathway.

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Section: Discussionmentioning

confidence: 99%

FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells

Zheng

Sun

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…Our data further emphasized the impact of oncogenic Src on diverse cellular processes. While Src is a known regulator of cytoskeletal organization, our work significantly extends our knowledge of downstream kinase mediators to include three members of the MARK family 30 , and the atypical CDK, CDK18 31 . The Src-regulated kinome also included kinases implicated in regulation of cell metabolism (e.g.…”

Section: Resultsmentioning

confidence: 97%

Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation

Zhang

Song

et al. 2019

Nat Commun

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Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an example, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identifies nine kinases, including SGK1, as being essential for Src-induced transformation. Accordingly, we find that Src positively regulates SGK1 expression in triple negative breast cancer cells, which exhibit a prominent signalling network governed by Src family kinases. Furthermore, combined inhibition of Src and SGK1 reduces colony formation and xenograft growth more effectively than either treatment alone. Therefore, this approach not only provides mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.

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“…They control localization of AQP2 and proliferation of the principal cells. In HEK293 cells, the knockdown of CDK18 caused RhoA activation [80]. Active RhoA prevents the accumulation of AQP2 in the plasma membrane of renal collecting duct principal cells [28].…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP

Dema

Faust

Lazarow

et al. 2020

Cells

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Arginine-vasopressin (AVP) facilitates water reabsorption in renal collecting duct principal cells through regulation of the water channel aquaporin-2 (AQP2). The hormone binds to vasopressin V2 receptors (V2R) on the surface of the cells and stimulates cAMP synthesis. The cAMP activates protein kinase A (PKA), which initiates signaling that causes an accumulation of AQP2 in the plasma membrane of the cells facilitating water reabsorption from primary urine and fine-tuning of body water homeostasis. AVP-mediated PKA activation also causes an increase in the AQP2 protein abundance through a mechanism that involves dephosphorylation of AQP2 at serine 261 and a decrease in its poly-ubiquitination. However, the signaling downstream of PKA that controls the localization and abundance of AQP2 is incompletely understood. We carried out an siRNA screen targeting 719 kinase-related genes, representing the majority of the kinases of the human genome and analyzed the effect of the knockdown on AQP2 by high-content imaging and biochemical approaches. The screening identified 13 hits whose knockdown inhibited the AQP2 accumulation in the plasma membrane. Amongst the candidates was the so far hardly characterized cyclin-dependent kinase 18 (CDK18). Our further analysis revealed a hitherto unrecognized signalosome comprising CDK18, an E3 ubiquitin ligase, STUB1 (CHIP), PKA and AQP2 that controls the localization and abundance of AQP2. CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. STUB1 functions as an A-kinase anchoring protein (AKAP) tethering PKA to the protein complex and bridging AQP2 and CDK18. The modulation of the protein complex may lead to novel concepts for the treatment of disorders which are caused or are associated with dysregulated AQP2 and for which a satisfactory treatment is not available, e.g., hyponatremia, liver cirrhosis, diabetes insipidus, ADPKD or heart failure.

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PCTK3/CDK18 regulates cell migration and adhesion by negatively modulating FAK activity

Cited by 27 publications

References 56 publications

FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells

FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells

Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation

Cyclin-Dependent Kinase 18 Controls Trafficking of Aquaporin-2 and Its Abundance through Ubiquitin Ligase STUB1, Which Functions as an AKAP

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