Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2

Blume, Julia von; Knippschild, Uwe; Dequiedt, Samuel; Giamas, Georgios; Beck, Alexander; Auer, Alexandra; Lint, Johan Van; Adler, Guido; Seufferlein, Thomas

doi:10.1038/sj.emboj.7601891

Cited by 46 publications

(45 citation statements)

References 36 publications

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“…4). This protein is known to phosphorylate protein kinase D2; active protein kinase D2 is trapped in the nucleus by CK1Â-induced phosphorylation leading to derepression of the apoptosis-inducing Nur77 (17). For the first time the present finding reports a CK1Â reduction in HCC suggesting a decreased pro-apoptotic activity of Nur77 that may in turn promote malignant hepatocyte proliferation.…”

Section: Discussionsupporting

confidence: 48%

Differential proteomic analysis of hepatocellular carcinoma

Corona¹,

Lorenzo²,

Elia³

et al. 2009

Int J Oncol

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Abstract. The principal aim of the present study consisted in the identification of the disregulated proteins associated with the development of hepatocellular carcinoma (HCC). The differences in protein expression between hepatocellular carcinoma (HCC) and the corresponding non-HCC liver tissues were investigated in a cohort of 20 patients using twodimensional fluorescence difference in gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS). The upand down-regulated protein spots that exhibited 1.5-fold difference signal intensity with statistical significance (p<0.05, t-test, confidence intervals 95%) were excised from the gel and identified by peptide mass fingerprinting using matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Thirty-six protein spots corresponding to 29 different disregulated proteins, belonging to heterogeneous metabolic pathways, have been identified. Down-regulated proteins (n=23) were found superior in number than the up-regulated proteins (n=6). Detoxification, carbohydrate metabolism and amino acid biotrasformation represented the main disregulated pathways in HCC. Upregulation of aldo-keto reductase 1C2, thioredoxin and transketolase, involved in metabolic and regulatory cellular processes including proliferation, differentiation and carcinogenesis were remarkable. These proteins could represent useful biomarkers to provide new insights into global pathophysiologic changes of HCC and for the development of new pharmacological approaches to HCC therapy.

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Section: Discussionsupporting

confidence: 48%

Differential proteomic analysis of hepatocellular carcinoma

Corona¹,

Lorenzo²,

Elia³

et al. 2009

Int J Oncol

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“…2B, panels AЈ-FЈ). Active PKD2 is known to phosphorylate nuclear substrates (27). However, interaction of wild type PKD2 and Snail1 was barely detectable.…”

Section: Resultsmentioning

confidence: 96%

Protein Kinase D1 Mediates Anchorage-dependent and -independent Growth of Tumor Cells via the Zinc Finger Transcription Factor Snail1

Eiseler

Köhler

Nimmagadda

et al. 2012

Journal of Biological Chemistry

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Background:The protein kinase D (PKD) family is involved in the control of cell motility and proliferation. Results: PKD1 controls growth of cancer cells through phosphorylation of Snail1 at Ser-11. Conclusion: Only PKD1, but not PKD2, mediates isoform-specific control of pancreatic cancer cell proliferation through Snail1. Significance: We demonstrate for the first time isoform-specific control of pancreatic cancer growth by a single phosphorylation of a substrate.

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“…For proteins that are shuttled in and out of the nucleus, the subcellular localization can be modulated via the phosphorylation of specific amino acid residues close to the NLS or NES (42)(43)(44)(45)(46). Phosphorylation may lead to a "masking" of the NLS (47,48) or an inhibition of the interaction between the CRM1 and NES (46). Alternatively, the phosphorylation of a nuclear factor may create a novel recognition site for a cytoplasmic protein, resulting in the cytosolic sequestration of the nuclear factor (49).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation by Casein Kinase 1 Regulates Tonicity-induced Osmotic Response Element-binding Protein/Tonicity Enhancer-binding Protein Nucleocytoplasmic Trafficking

Wong

Tong

et al. 2008

Journal of Biological Chemistry

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The osmotic response element-binding protein (OREBP), also known as tonicity enhancer-binding protein (TonEBP) or NFAT5, is the only known osmo-sensitive transcription factor that mediates cellular adaptations to extracellular hypertonic stress. Although it is well documented that the subcellular localization and transactivation activity of OREBP/TonEBP are tightly regulated by extracellular tonicity, the molecular mechanisms involved remain elusive. Here we show that nucleocytoplasmic trafficking of OREBP/TonEBP is regulated by the dual phosphorylation of Ser-155 and Ser-158. Alanine scanning mutagenesis revealed that Ser-155 is an essential residue that regulates OREBP/TonEBP nucleocytoplasmic trafficking. Tandem mass spectrometry revealed that Ser-155 and Ser-158 of OREBP/TonEBP are both phosphorylated in living cells under hypotonic conditions. In vitro phosphorylation assays further suggest that phosphorylation of the two serine residues proceeds in a hierarchical manner with phosphorylation of Ser-155 priming the phosphorylation of Ser-158 and that these phosphorylations are essential for nucleocytoplasmic trafficking of the transcription factor. Finally, we have shown that the pharmacological inhibition of casein kinase 1 (CK1) abolishes the phosphorylation of Ser-158 and impedes OREBP/TonEBP nuclear export and that recombinant CK1 phosphorylates Ser-158. Knockdown of CK1␣1L, a novel isoform of CK1, inhibits hypotonicity-induced OREBP/TonEBP nuclear export. Together these data highlight the importance of Ser-155 and Ser-158 in the nucleocytoplasmic trafficking of OREBP/TonEBP and indicate that CK1 plays a major role in regulating this process.The osmotic response element-binding protein (OREBP), 3 also known as TonEBP, belongs to the Rel family of transcription factors that includes NFB and nuclear factor of activated T cells (NFAT). Members of this family contain a Rel homology domain for DNA binding (1, 2). Because the Rel homology domain of OREBP/TonEBP shares significant homology to that of other NFAT isoforms (NFAT1-4), it was independently identified by homology screening and named NFAT5 (3). However, unlike NFAT1-4, OREBP/TonEBP lacks the calcineurin binding domain that plays a critical role in regulating the subcellular localization and activity of the NFATs (4). Although NFAT-1, -2, and -4 regulate the immune response as well as the development of heart, bone, thymus, and the nervous system (5, 6), OREBP/TonEBP plays a pivotal role in activating adaptive cellular responses to extracellular hypertonic stress (2, 7).OREBP/TonEBP is the only known osmo-sensitive transcription factor in mammalian cells. Upon activation by hypertonic stress, it induces the expression of a battery of osmoprotective genes, including aldose reductase, the betaine/ ␥-aminobutyric acid transporter, and the Na ϩ -dependent myoinositol transporter, through binding to a cognate cis-acting element known as the osmotic response element or the tonicity-responsive enhancer (8 -11) in the promoter region of these genes. Consequent...

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Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2

Cited by 46 publications

References 36 publications

Differential proteomic analysis of hepatocellular carcinoma

Differential proteomic analysis of hepatocellular carcinoma

Protein Kinase D1 Mediates Anchorage-dependent and -independent Growth of Tumor Cells via the Zinc Finger Transcription Factor Snail1

Phosphorylation by Casein Kinase 1 Regulates Tonicity-induced Osmotic Response Element-binding Protein/Tonicity Enhancer-binding Protein Nucleocytoplasmic Trafficking

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