The role of the casein kinase 1 (CK1) family in different signaling pathways linked to cancer development
ABSTRACT The members of the casein kinase 1 (CK1) family are highly conserved and are expressed in many eukaryotes ranging from yeast to humans. Mammalian CK1 isoforms (alpha, beta, gamma, delta, epsilon) and their splice variants are involved in diverse cellular processes including membrane trafficking, circadian rhythm, cell cycle progression, chromosome segregation, apoptosis and cellular differentiation. Mutations and deregulation of CK1 expression and activity has been linked to various diseases including neurodegenerative disorders such as Alzheimer's and Parkinson's disease, sleeping disorders and proliferative diseases such as cancer. In this review, we summarize the functions of CK1 and outline the participation of CK1 in signal transduction pathways linked to cancer development.
- SourceAvailable from: Homa Ghalei
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- "CK1/CK1 are targets for the development of novel chemotherapeutics against cancer and neurodegenerative diseases (Knippschild et al., 2005b, 2014; Perez et al., 2011). Importantly , some CK1/CK1 inhibitors have potent antiproliferative effects ex vivo, and lead to tumor regression and improved survival in preclinical animal cancer models (Knippschild et al., 2014). "
ABSTRACT: Casein kinase 1δ/ε (CK1δ/ε) and their yeast homologue Hrr25 are essential for cell growth. Further, CK1δ is overexpressed in several malignancies, and CK1δ inhibitors have shown promise in several preclinical animal studies. However, the substrates of Hrr25 and CK1δ/ε that are necessary for cell growth and survival are unknown. We show that Hrr25 is essential for ribosome assembly, where it phosphorylates the assembly factor Ltv1, which causes its release from nascent 40S subunits and allows subunit maturation. Hrr25 inactivation or expression of a nonphosphorylatable Ltv1 variant blocked Ltv1 release in vitro and in vivo, and prevented entry into the translation-like quality control cycle. Conversely, phosphomimetic Ltv1 variants rescued viability after Hrr25 depletion. Finally, Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due, at least in part, to disruption of ribosome assembly. These findings validate the ribosome assembly pathway as a novel target for the development of anticancer therapeutics. © 2015 Ghalei et al.The Journal of Cell Biology 03/2015; 208(6):745-59. DOI:10.1083/jcb.201409056 · 9.69 Impact Factor
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- "Unlike other kinases such as Akt and mTOR , the activity of CKI is considered relatively constant in vivo. However, previous studies have demonstrated that, like many other kinases such as glycogen synthase kinase 3 or CKII, CKI requires a priming phosphorylation event at the −3 position for efficient phosphorylation of the substrate . Therefore, we reasoned that given the constant activity of CKI, the priming kinase might determine the timing of the CKI-mediated phosphorylation and subsequent destruction of the substrate. "
ABSTRACT: Deregulation of the mammalian target of rapamycin (mTOR) signaling pathway has been found in a variety of human cancers. However, the exact molecular mechanism how the mTOR signaling pathway is regulated remains largely elusive. Recently, DEPTOR was identified as an endogenous mTOR inhibitor that could suppress mTOR activity in vivo. More importantly, accumulated evidence has implicated that DEPTOR plays a pivotal role in the development and progression of human malignances, which could in part be mediated through its inhibitory role toward mTOR. Furthermore, three independent laboratories including our own have demonstrated that the stability of DEPTOR is controlled by the SCF(β-TrCP) E3 ubiquitin ligase and deregulated DEPTOR destruction might contribute to hyperactivation of mTOR in pathologic conditions including cancer. This review discusses the recent literature regarding the function of DEPTOR involved in cell growth, apoptosis, autophagy, epithelial-mesenchymal transition, and drug resistance, all of which are associated with the pathogenesis of human cancers. Moreover, we also summarize that targeting DEPTOR may be a novel strategy for achieving better anticancer treatments.Neoplasia (New York, N.Y.) 05/2012; 14(5):368-75. DOI:10.1593/neo.12542 · 5.40 Impact Factor
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- "CK1δ, a member of the CK1 kinase family and the mammalian counterpart of yeast Hrr25, is involved in the regulation of many different cellular processes, including cell proliferation and cell death , . Mutations and alterations in the expression and/or activity of CK1δ have been detected in various tumor entities, e.g. in adenocarcinomas of the pancreas , in mammary tumors  and in adenoid cystic carcinomas , suggesting that changes in CK1δ activity can contribute to carcinogenesis. As SV40 mediated transformation is a well established model to study cellular factors associated with the transformation process, we characterized the role of CK1δ in SV40 mediated transformation in a cell culture system and in the WAP-T transgenic mouse model –. "
ABSTRACT: Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data show that inactivating mutations in CK1δ impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.PLoS ONE 01/2012; 7(1):e29709. DOI:10.1371/journal.pone.0029709 · 3.23 Impact Factor