Protein kinase

Summary

A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other proteins. The human genome contains about 500 protein kinase genes and they constitute about 2% of all human genes. There are two main types of protein kinase. The great majority are serine/threonine kinases, which phosphorylate the hydroxyl groups of serines and threonines in their targets. Most of the others are tyrosine kinases, although additional types exist. Protein kinases are also found in bacteria and plants. Up to 30% of all human proteins may be modified by kinase activity, and kinases are known to regulate the majority of cellular pathways, especially those involv

Official source

https://en.wikipedia.org/wiki/Protein_kinase

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Identification and functional characterization of protein kinases that modulate Notch signaling under physiological conditions and in cancer

Chhavi Jain

The Notch signaling pathway is a key regulator of cell fate decisions in embryonic development and in adult tissue homeostasis. Mounting evidence suggests that Notch signaling is frequently deregulated in human neoplasms, where depending upon the cellular context it can function both as an oncogene or a tumor suppressor. A plethora of studies shed light on how Notch crosstalks with signaling pathways downstream to manifest either its oncogenic or tumor suppressive activity. However, regulatory networks upstream of the Notch signaling pathway are still poorly understood. Since protein kinases are well-known regulators of a majority of cell signaling pathways, the aim of the current study was to identify novel positive and negative regulatory kinases that modulate Notch signaling. Using a HeLa cell based co-culture assay to read Notch-dependent luciferase activity, a small interference RNA (siRNA) library against the human kinase genome was previously tested in a high-throughput manner. Validation of top candidate kinases from the screening using both siRNA as well as pharmacological inhibitors led to further elimination of false positives and identification of Protein Kinase B (AKT2) and Calmodulin Kinase II (CaMKII) as key positive while Janus kinases (JAKs) as key negative regulators of the Notch signaling pathway. In the first part of the study, we analyzed the positive regulation of AKT2 and CaMKII kinases on Notch signaling in the T-cell acute lymphoblastic leukemia (T-ALL) cells where Notch is oncogenic. It was shown that pharmacological inhibition of either AKT2 or CaMKII kinase in T-ALL cell lines in vitro abrogated the expression of active Notch1 intracellular domain (N1-ICD) as well as of Notch target genes. Moreover, inhibition of these kinases blocked proliferation of T-ALL cells. In the second part of the study, we analyzed the negative regulation of JAK kinases on Notch signaling using a distinct physiological context where Notch is tumor suppressive. It was shown that pharmacological inhibition of JAK kinases led to an induction of Notch receptor transcription and of Notch target genes in the human primary epidermal keratinocytes (HPEK) as well as in the skin squamous cell carcinoma (SCC) cell lines. In addition, the pharmacological inhibition of JAK kinases induced a block in proliferation, cell cycle arrest and differentiation in HPEKs and skin SCCs by increased expression of early differentiation markers. Suppression of Notch signaling in primary keratinocytes counteracted the differentiation-inducing effect of JAK inhibition. Since JAK inhibition affected Notch transcription, global gene expression profiling using RNA sequencing was done to identify transcription factors involved in an indirect regulation of JAK kinases on the Notch cascade. EGR1 and EGR2 belonging to the early growth response family of transcription factors were significantly modulated downstream of JAK inhibition. In vivo, topical inhibition of JAK kinases provided marked resistance against chemically induced cutaneous carcinogenesis.Taken together, our data reveals a key role of AKT2 and CaMKII kinases in positive regulation while of JAK kinases in the negative regulation of Notch signaling, of potential relevance for combinatory approaches for cancer therapy. Pharmacological inhibitors against these kinases could be tested for their ability to modulate Notch signaling and may prove highly beneficial in the therapy of Notch-driven cancers.

EPFL2016

In this study, the fission yeast Schizosaccharomyces pombe was used as a model system to study the cellular signaling that underlies cell cycle progression. Phosphorylation plays an important part in the regulation of this process. Kinases catalyze the transfer of a phosphate group to a substrate, which may regulate its activity. Protein phosphatases oppose the activity of protein kinases; the balance of their activities regulates signaling flux in many signaling pathways. The Septation Initiation Network (SIN) is a signaling cascade that regulates cytokinesis in fission yeast. SIN signaling is triggered by a GTPase and is transduced by three protein kinases; phosphorylation plays an important role in controlling SIN signalling. Numerous genetic screens and biochemical analyses have identified phosphatases and kinases that regulate the SIN. The protein phosphatases Calcineurin/Protein Phosphatase 2B (PP2B) and Flp1p promote SIN signaling, while PP2A is a SIN inhibitor. PP2A is conserved and is activated by the chaperone Phosphatase Two A Phosphatase Activator (PTPA). S. pombe has two PTPA-related genes, ypa1 and ypa2; the deletion mutant of the latter rescues SIN mutants which cannot undergo cytokinesis, consistent with PP2A opposing SIN signaling. The phenotype of the deletion mutant of ypa2, indicates that it is involved in the control of cell polarity, cell growth, mitotic commitment and cytokinesis. In this study, we characterized the hypomorphic allele ypa2-S2 which rescues SIN mutants, but is otherwise largely normal. ypa2-s2 was used as bait in a synthetic genetic array screen, to identify genes whose products compensate for reduced function of Ypa2p. A large number of hits were identified, of which approximately ninety percent are novel genetic interactors of ypa2. Validation studies indicated that eighty percent of the interactions seen in the high-throughput screen can be reconstructed. The identified genes regulate several biological processes, including signal transduction and protein phosphorylation. This prompted us to further characterize the roles of Ckb1p and Flp1p, in regulating cytokinesis signaling. Ckb1p is a regulatory subunit for Casein Kinase II (CK II), which was previously implicated in polar growth. The phenotype of the mutant ypa2-S2 ckb1-â indicates that Ckb1p, similar to Ypa2p, contributes to the regulation of mitotic commitment and cytokinesis signaling. Furthermore, ckb1-â showed negative genetic interaction with PP2A and SIN mutants. Flp1p is a protein phosphatase that was reported to regulate mitotic commitment and to promote SIN signaling. The double mutant between ypa2-S2 and flp1-â showed cell separation defects and phenotypic analysis of double mutants between flp1-â and PP2A mutants indicates that these phosphatases cooperate in cell separation. Overall, this work has uncovered novel facets of the regulation of cytokinesis in S. pombe, implicating CK II in controlling SIN signaling, and uncovering cooperative interactions between different phosphatases in controlling cytokinesis.

EPFL2016

Regulation of the protein complex NEEP21 - GRIP - GluR2 implicated in AMPAR trafficking through endosomal compartments

Karina Kulangara

It is important for neurotransmission to control the number of receptors at synapses. The synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors (AMPARs) control the strength of excitatory transmission. These receptors are mobile and cycle between internal endosomal compartments and the plasma membrane. We have identified previously a protein complex between the endosomal protein NEEP21, the AMPAR subunit GluR2 and the scaffold protein GRIP necessary for correct GluR2 recycling. Here we elucidate the regulation underlying the complex formation and dissociation necessary for the trafficking through endosomal compartments. We show that a 85 kDa protein kinase, which is associated with NEEP21, phosphorylates GRIP on serine 917. Protein kinase C is activated by glutamate receptor stimulation, and leads to the activation of the NEEP21-associated kinase. The phosphorylation of GRIP leads to a reduced binding between GRIP and NEEP21, and GRIP and GluR2. Serine 917 is implicated in AMPAR cycling, since a wildtype carboxyterminal GRIP fragment expressed in hippocampal neurons interferes with GluR2 surface expression. On the contrary, a S917D mutant fragment does not interfere with GluR2 surface expression. The regulation of the formation and dissociation of the protein complex between NEEP21, GluR2 and GRIP1 may suggest a sorting mechanism between the recycling and degradation pathways for the AMPAR subunit GluR2. This is especially important in the light of the discovery of a form of plasticity which implicates GluR2-lacking AMPAR, and the fact that insertion of GluR2-lacking AMPAR are implicated in a number of neurological diseases like ALS or ischemia. Our results identify an important regulatory mechanism in the trafficking of AMPAR subunits between internal compartments and the plasma membrane.

EPFL2006

Regulation of the protein complex NEEP21 - GRIP - GluR2 implicated in AMPAR trafficking through endosomal compartments

Karina Kulangara

EPFL2006

Identification and functional characterization of protein kinases that modulate Notch signaling under physiological conditions and in cancer

Chhavi Jain

EPFL2016