PCTAIRE Kinase 3/Cyclin-dependent Kinase 18 Is Activated through Association with Cyclin A and/or Phosphorylation by Protein Kinase A

Matsuda, Shinya; Kominato, Kyohei; Koide-Yoshida, Shizuyo; Miyamoto, K.; Isshiki, Kinuka; Tsuji, Akihiko; Yuasa, Keizo

doi:10.1074/jbc.m113.542936

Cited by 26 publications

(35 citation statements)

References 53 publications

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“…Intracellular cAMP is thought to inhibit T cell activation and proliferation via activation of the cAMP-dependent PKA, and among the several immunologic factors that contribute to susceptibility to HIV infection, increasing evidence suggests that cAMP and downstream signaling via PKA play a crucial role [54]. In addition, PKA regulates cell proliferation via alteration of the cyclin/cyclin-dependent kinase complex [55,56]. Interestingly, our unpublished data from characterization of the METH effects on T cell cycle entry and progression show that it results in altered cell-cycle entry and progression and decreased expression of cell-cycle progression markers (cyclin and cyclindependent kinase) of CD4 + and CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Sriram

Cenna

Haldar

et al. 2015

Journal of Leukocyte Biology

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The novel transmembrane G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), represents a potential, direct target for drugs of abuse and monoaminergic compounds, including amphetamines. For the first time, our studies have illustrated that there is an induction of TAAR1 mRNA expression in resting T lymphocytes in response to methamphetamine. Methamphetamine treatment for 6 h significantly increased TAAR1 mRNA expression (P < 0.001) and protein expression (P < 0.01) at 24 h. With the use of TAAR1 gene silencing, we demonstrate that methamphetamine-induced cAMP, a classic response to methamphetamine stimulation, is regulated via TAAR1. We also show by TAAR1 knockdown that the down-regulation of IL-2 in T cells by methamphetamine, which we reported earlier, is indeed regulated by TAAR1. Our results also show the presence of TAAR1 in human lymph nodes from HIV-1-infected patients, with or without a history of methamphetamine abuse. TAAR1 expression on lymphocytes was largely in the paracortical lymphoid area of the lymph nodes with enhanced expression in lymph nodes of HIV-1-infected methamphetamine abusers rather than infected-only subjects. In vitro analysis of HIV-1 infection of human PBMCs revealed increased TAAR1 expression in the presence of methamphetamine. In summary, the ability of methamphetamine to activate trace TAAR1 in vitro and to regulate important T cell functions, such as cAMP activation and IL-2 production; the expression of TAAR1 in T lymphocytes in peripheral lymphoid organs, such as lymph nodes; and our in vitro HIV-1 infection model in PBMCs suggests that TAAR1 may play an important role in methamphetamine -mediated immune-modulatory responses.

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Section: Discussionmentioning

confidence: 99%

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Sriram

Cenna

Haldar

et al. 2015

Journal of Leukocyte Biology

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“…CDK18 was induced by CTS-1 (Chimeric tumor suppressor-1, p53derived synthetic tumor suppressor) and mediated growth arrest and death in glioma cells [61]. Apart from its activation by cyclin A2, in the same study CDK18 was shown to phosphorylate retinoblastoma tumorsupressor protein (Rb) in vitro [55]. Although PCTAIRE1 has been found to be upregulated in many cancers, so far there is no such data for CDK18.…”

Section: Cdk18 Ccnd1 Loxmentioning

confidence: 98%

“…PCTAIRE kinase subfamily includes three members, PCTK1/CDK16, PCTK2/CDK17, and PCTK3/CDK18 which are poorly researched. Insights into the activation of CDK18 have recently been obtained-it binds cyclin A2 and cyclin E1 (pulldown experiment with HEK293T cells) and is activated by cyclin A2 and PKA (cAMP-dependent protein kinase) [55]. CDK18 has recently been shown to regulate cell migration and adhesion in HEK293T cells by negatively modulating FAK (focal adhesion kinase) activity and reorganizing actin and associated skeletal/adhesion proteins such as cofilin, and has also been implicated in vesicular transport via interaction with Sec23Ap [56].…”

Section: Cdk18 Ccnd1 Loxmentioning

confidence: 99%

Limited utility of qPCR-based detection of tumor-specific circulating mRNAs in whole blood from clear cell renal cell carcinoma patients

et al. 2020

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Background: RNA sequencing data is providing abundant information about the levels of dysregulation of genes in various tumors. These data, as well as data based on older microarray technologies have enabled the identification of many genes which are upregulated in clear cell renal cell carcinoma (ccRCC) compared to matched normal tissue.Here we use RNA sequencing data in order to construct a panel of highly overexpressed genes in ccRCC so as to evaluate their RNA levels in whole blood and determine any diagnostic potential of these levels for renal cell carcinoma patients.Methods: A bioinformatics analysis with Python was performed using TCGA, GEO and other databases to identify genes which are upregulated in ccRCC while being absent in the blood of healthy individuals. Quantitative Real Time PCR (RT-qPCR) was subsequently used to measure the levels of candidate genes in whole blood (PAX gene) of 16 ccRCC patients versus 11 healthy individuals. PCR results were processed in qBase and GraphPadPrism and statistics was done with Mann-Whitney U test. Results: While most analyzed genes were either undetectable or did not show any dysregulated expression, two genes, CDK18 and CCND1, were paradoxically downregulated in the blood of ccRCC patients compared to healthy controls. Furthermore, LOX showed a tendency towards upregulation in metastatic ccRCC samples compared to nonmetastatic.Conclusions: This analysis illustrates the difficulty of detecting tumor regulated genes in blood and the possible influence of interference from expression in blood cells even for genes conditionally absent in normal blood. Testing in plasma samples indicated that tumor specific mRNAs were not detectable. While CDK18, CCND1 and LOX mRNAs might carry biomarker potential, this would require validation in an independent, larger patient cohort.

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“…PKA phosphorylates CDK18 at S12, S66 and S109. The phosphorylation at S12 increases CDK18 activity even in the absence of the activating cofactor Cyclin A2 [54]. We evaluated the PKA phosphorylation of CDK18 by immunoprecipitation of the kinase and detection by Western blotting with phospho-PKA substrate antibodies.…”

Section: Avp Induces Pka-dependent Increases Of Cdk18 Phosphorylationmentioning

confidence: 99%

“…The data indicated that the cAMPmediated activation of PKA increased CDK18 kinase phosphorylation and its protein abundance, and presumably CDK18 activity ( Figure 2B). To investigate whether CDK18 phosphorylates AQP2 at S261, FLAG-tagged CDK18 as wild type (Wt), constitutively active (Ser12Asp; S12D, mimicking activation by PKA-mediated phosphorylation) and kinase dead (Lys150Arg; K150R) forms [54] were expressed in and purified from HEK293 cells through precipitation via their Flag tags. The activity of the Wt CDK18 and the constitutively active S12D versions were confirmed by their ability to phosphorylate a spot-synthesised peptide substrate derived from the retinoblastoma (Rb) protein ( Figure 3A).…”

Section: Cdk18 Controls the Phosphorylation Of Aqp2 At S261 Its Ubiqmentioning

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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PCTAIRE Kinase 3/Cyclin-dependent Kinase 18 Is Activated through Association with Cyclin A and/or Phosphorylation by Protein Kinase A

Cited by 26 publications

References 53 publications

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation

Limited utility of qPCR-based detection of tumor-specific circulating mRNAs in whole blood from clear cell renal cell carcinoma patients

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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