Nek family of kinases in cell cycle, checkpoint control and cancer

Early studies in lower Eukaryotes have defined a role for the members of the NimA related kinase (Nek) family of protein kinases in cell cycle control. Expansion of the Nek family throughout evolution has been accompanied by their broader involvement in checkpoint regulation and cilia biology. Moreover, mutations of Nek family members have been identified as drivers behind the development of ciliopathies and cancer. Recent advances in studying the physiological roles of Nek family members utilizing mouse genetics and RNAi-mediated knockdown are revealing intricate associations of Nek family members with fundamental biological processes. Here, we aim to provide a comprehensive account of our understanding of Nek kinase biology and their involvement in cell cycle, checkpoint control and cancer

Understanding the benefit of metformin use in cancer treatment

Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR) signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed

Regulation of glycogen synthase kinase-3

grantor: University of TorontoGlycogen synthase kinase-3 (GSK-3) represents a family of protein serine/threonine protein kinases implicated in cellular regulation. GSK-3 family members participate in a number of signal transduction pathways that regulate cell growth, differentiation and development. The high degree of conservation between GSK-3 proteins, as well as their ubiquitous representation, indicates a fundamental role of this kinase family in regulation of cellular processes. The presented studies are aimed at elucidating different aspects of regulation of GSK-3. A mechanism of inhibition of GSK-3 in intact cells by phosphorylation of an N-terminal serine is revealed. N-terminal phosphorylation might represent a common mechanism of negative regulation of GSK-3 enzymes in vivo, since phosphorylation of a homologous serine in several other GSK-3 family members is also inhibitory. Stimulation of cells by the agonists of the ras signalling pathway downregulates GSK-3 via N-terminal phosphorylation by p90rsk-1, implicating GSK-3 as one of the targets of this important cellular regulatory cascade. During development, exposure of eukaryotic cells to lithium ions causes marked effects on cellular fate and organization, similar to the effects of inhibition or disruption of GSK-3. Results presented here demonstrate that lithium specifically inhibits GSK-3 family members in vitro and in intact cells, implying that this may be the dominant cellular action of the ion. The effect of lithium on GSK-3 is reversible in vitro indicating a direct mechanism of inactivation. Furthermore, lithium treatment of cells mimics Wingless/Wnt signalling, consistent with its role in downregulation of GSK-3. Using a novel method for the analysis of activity of protein kinases in intact Drosophila embryos, it is shown that the Drosophila GSK-3 homologue is inhibited in response to the Wingless signal. A cotransfection approach in mammalian cells indicates that overexpression of another genetically identified component of Wingless signalling upstream of GSK-3, Dishevelled, does not affect GSK-3 activity. The implications of novel modes of GSK-3 regulation on its cellular functions are discussed.Ph.D

Nek10 Mediates G2/M Cell Cycle Arrest and MEK Autoactivation in Response to UV Irradiation▿

Appropriate cell cycle checkpoint control is essential for the maintenance of cell and organismal homeostasis. Members of the Nek (NIMA-related kinase) family of serine/threonine protein kinases have been implicated in the regulation of various aspects of the cell cycle. We explored the cellular functions of Nek10, a novel member of the Nek family, and demonstrate a role for Nek10 in the cellular UV response. Nek10 was required for the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling upon UV irradiation but not in response to mitogens, such as epidermal growth factor stimulation. Nek10 physically associated with Raf-1 and MEK1 in a Raf-1-dependent manner, and the formation of this complex was necessary for Nek10-mediated MEK1 activation. Nek10 did not affect the kinase activity of Raf-1 but instead promoted the autophosphorylation-dependent activation of MEK1. The appropriate maintenance of the G2/M checkpoint following UV irradiation required Nek10 expression and ERK1/2 activation. Taken together, our results uncover a role for Nek10 in the cellular response to UV irradiation

Nek family of kinases in cell cycle, checkpoint control and cancer

Abstract Early studies in lower Eukaryotes have defined a role for the members of the NimA related kinase (Nek) family of protein kinases in cell cycle control. Expansion of the Nek family throughout evolution has been accompanied by their broader involvement in checkpoint regulation and cilia biology. Moreover, mutations of Nek family members have been identified as drivers behind the development of ciliopathies and cancer. Recent advances in studying the physiological roles of Nek family members utilizing mouse genetics and RNAi-mediated knockdown are revealing intricate associations of Nek family members with fundamental biological processes. Here, we aim to provide a comprehensive account of our understanding of Nek kinase biology and their involvement in cell cycle, checkpoint control and cancer