Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-β signaling

X, Guo; Waddell, David; Wang, W; Wang, Z; Nt, Liberati; Yong, Sheila T.; Liu, Xuedong; Xf, Wang

doi:10.1038/onc.2008.337

Cited by 33 publications

(30 citation statements)

References 46 publications

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“…In addition, expression of CKI␥2 reduced the synthesis of SM, whereas knockdown of endogenous CKI␥2 failed to show the increased synthesis of SM because the knockdown significantly caused cell death. This may reflect its important roles in the regulation of various cellular processes (Davidson et al, 2005;Knippschild et al, 2005;Guo et al, 2008). Instead, we showed that expression of CERT S132A enhances the synthesis of SM in CHO/vector cells ( Figure 5, B and C).…”

Section: Discussionmentioning

confidence: 56%

Casein Kinase Iγ2 Down-Regulates Trafficking of Ceramide in the Synthesis of Sphingomyelin

Tomishige

Kumagai

Kusuda

et al. 2009

MBoC

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Intracellullar trafficking of lipids is fundamental to membrane biogenesis. For the synthesis of sphingomyelin, ceramide is transported from the endoplasmic reticulum to the Golgi apparatus by the ceramide transfer protein CERT. CERT is phosphorylated by protein kinase D at S132 and subsequently multiple times in a serine-repeat motif, resulting in its inactivation. However, the kinase involved in the multiple phosphorylation remains unclear. Here, we identify the ␥2 isoform of casein kinase I (CKI␥2) as a kinase whose overexpression confers sphingomyelin-directed toxin-resistance to Chinese hamster ovary cells. In a transformant stably expressing CKI␥2, CERT was hyperphosphorylated, and the intracellular trafficking of ceramide was retarded, thereby reducing de novo sphingomyelin synthesis. The reduction in the synthesis of sphingomyelin caused by CKI␥2 was reversed by the expression of CERT mutants that are not hyperphosphorylated. Furthermore, CKI␥2 directly phosphorylated CERT in vitro. Among three ␥ isoforms, only knockdown of ␥2 isoform caused drastic changes in the ratio of hypo-to hyperphosphorylated form of CERT in HeLa cells. These results indicate that CKI␥2 hyperphosphorylates the serine-repeat motif of CERT, thereby inactivating CERT and down-regulating the synthesis of sphingomyelin.

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Section: Discussionmentioning

confidence: 56%

Casein Kinase Iγ2 Down-Regulates Trafficking of Ceramide in the Synthesis of Sphingomyelin

Tomishige

Kumagai

Kusuda

et al. 2009

MBoC

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“…This data agrees with the idea that some casein kinases participate in endoplasmic reticulum stress signaling via phosphorylation of different proteins which are important components of IRE-1 signaling [10,28,33]. We have found that the expression of different casein kinase-1 isoenzymes change in different ways in IRE-1α knockdown glioma cells and, it is quite possible, that this dysregulation is responsible for the suppression of proliferation of these cells [14], because different isoforms of casein kinase-1 (alpha, gamma-1, and delta) participate in the regulation of the Wnt and TGF-beta signaling cascades, in phosphorylation of TP53 [33,35,36]. Moreover, suppression of IRE-1α function in glioma cells also leads to a decrease of the catalytic subunit of casein kinase-2 (CSNK2A1) which has an important regulatory function in cell proliferation, cell differentiation, and in apoptosis via phosphorylation of a number of key intracellular signaling proteins implicated in tumorigenesis and tumor suppression [37].…”

Section: Discussionmentioning

confidence: 97%

“…It was also shown that three isoforms of casein kinase-1 (alpha, gamma-1 and delta) participate in phosphorylation of the N-terminal region of TP53 [35]. There is data that casein kinase-1 gamma 2, an inhibitor of TGF-beta signaling, regulates ligand-dependent ubiquitynation of Smad3 [36].…”

Section: Introductionmentioning

confidence: 99%

Expression of casein kinase genes in glioma cell line U87: Effect of hypoxia and glucose or glutamine deprivation

Minchenko¹,

Karbovskyi²,

Danilovskyi³

et al. 2012

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The endoplasmic reticulum-nuclei-1 (ERN1) sensing and signaling enzyme mediates a set of complex intracellular signaling events known as the unfolded protein response. We have studied the effect of hypoxia and ischemic conditions (glucose or glutamine deprivation) on the expression of several casein kinase-1 and -2 genes in glioma U87 cells and its subline with suppressed function of ERN1. It was shown that blockade of ERN1, the key endoplasmic reticulum stress sensor, leads to an increase in the expression levels of casein kinase-1G2, -1E, -2B and NUCKS1 mRNA, but suppresses casein kinase-1A1, -1D and -2A1. Moreover, the expression levels of casein kinase-1A1, -1D and 1G3 as well as casein kinase-2A1 and -2A2 mRNAs are significantly increased under glutamine deprivation conditions both in control and ERN1-deficient glioma cells. At the same time, casein kinase-1E, -2B and NUCKS1 mRNA expression levels are also increased under this condition, but only in cells with suppressed function of ERN1. The expression level of NUCKS1 mRNA, however, is decreased both in control glioma cells and in genetically modified cells, but casein kinase-1G2-only in control U87 cells. Cell exposure to glucose deprivation conditions enhances the expression levels of casein kinase-1D, 1G3, -1E and -2A1 in both types of glioma cells used, but casein kinase-2B expression levels increase only in cells with suppressed function of ERN1. Hypoxia induces or suppresses the expression of most of the studied genes mainly in ERN1-knockdown cells only. Results of this study show that hypoxia as well as glutamine and glucose deprivation conditions change the expression level most of casein kinase genes and that these effects are dependent on ERN1 signaling enzyme function.

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“…This phosphorylation is followed by the ubiquitylation and proteasomal degradation of SMAD3, which regulate its steady-state levels. By contrast, upon TGF receptor phosphorylation, SMAD3 can be further phosphorylated in its MH2 domain by casein kinase 1 2, which leads to the specific ubiquitylation and degradation of the activated form of SMAD3 (Guo et al, 2008b).A recent report has shed more light on the complexity of Smad regulation through the phosphorylation of its linker domain (Wang et al, 2009). After SMAD3 C-terminal phosphorylation by TRI in mammalian cells, nuclear GSK3 and cyclin-dependent kinases phosphorylate three distinct SMAD3 linker residues, downregulating its transcriptional activity.…”

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confidence: 99%

The regulation of TGFβ signal transduction

2009

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Transforming growth factor  (TGF) pathways are implicated in metazoan development, adult homeostasis and disease. TGF ligands signal via receptor serine/threonine kinases that phosphorylate, and activate, intracellular Smad effectors as well as other signaling proteins. Oligomeric Smad complexes associate with chromatin and regulate transcription, defining the biological response of a cell to TGF family members. Signaling is modulated by negative-feedback regulation via inhibitory Smads. We review here the mechanisms of TGF signal transduction in metazoans and emphasize events crucial for embryonic development. IntroductionThe human transforming growth factor  (TGF) family consists of 33 members, most of which encode dimeric, secreted polypeptides that control developmental processes, ranging from gastrulation and body axis asymmetry to organ-specific morphogenesis and adult tissue homeostasis (reviewed by Derynck and Miyazono, 2008). In addition to TGFs, this family includes the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins and nodal. The TGF family is conserved throughout metazoan evolution. At the cellular level, TGF family members regulate cell growth, differentiation, adhesion, migration and death, in a developmental context-dependent and cell type-specific manner. For example, TGF more often inhibits, but sometimes also stimulates, cell proliferation (reviewed by Yang and Moses, 2008). Furthermore, nodal signaling sometimes inhibits, whereas BMP promotes, cell differentiation, as in stem cells (Watabe and Miyazono, 2009). As TGF ligands act multifunctionally in numerous tissue types, they also play complex roles in various human diseases, ranging from autoimmune to cardiovascular diseases and cancer (reviewed by Gordon and Blobe, 2008;Massagué, 2008).Here we review the core components of the TGF family and their signaling engines, as part of a Minifocus in this issue on TGF signaling (see Box 1), and discuss emerging concepts concerning the regulatory mechanisms of TGF pathways at the receptor, cytoplasmic and nuclear level. We also highlight recent discoveries that are of particular developmental relevance. The TGF familyThe development of the axes and the asymmetry of the animal body depends on the localized action of extracellular signals, such as the Wnt, nodal and BMP ligands. Gradients of these ligands, their extracellular regulators and the competence of receptors in responding cells, play important roles during tissue morphogenesis (Affolter and Basler, 2007;Smith and Gurdon, 2004). TGF family members also contribute to tissue patterning and are important regulators of stem cell self-renewal and differentiation (see Box 2) (De Robertis and Kuroda, 2004;Watabe and Miyazono, 2009).The TGF morphogens include numerous secreted and conserved polypeptides (Table 1), which emerged at the onset of multicellular (metazoan) life (Huminiecki et al., 2009). Structurally, this family is characterized by a specific three-dimensional fold and by a conser...

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Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-β signaling

Cited by 33 publications

References 46 publications

Casein Kinase Iγ2 Down-Regulates Trafficking of Ceramide in the Synthesis of Sphingomyelin

Casein Kinase Iγ2 Down-Regulates Trafficking of Ceramide in the Synthesis of Sphingomyelin

Expression of casein kinase genes in glioma cell line U87: Effect of hypoxia and glucose or glutamine deprivation

The regulation of TGFβ signal transduction

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