• MAPK
  • p90 ribosomal S6 kinase (RSK), a serine threonine kinase that lies downstream of the Ras-MAPK (mitogen activated protein kinase) cascade, has been demonstrated to be involved in the regulation of cell proliferation in various malignancies through indirect (e.g., modulation of transcription factors) or direct effects on the cell-cycle machinery. (biomedcentral.com)
  • p38 MAP Kinase (MAPK), also called RK or CSBP (Cytokinin Specific Binding Protein), is the mammalian orthologue of the yeast Hog1p MAP kinase, which participates in a signaling cascade controlling cellular responses to cytokines and stress. (wikipedia.org)
  • The p38 mitogen-activated protein kinase (MAPK) is a key mediator in cytokine-induced signaling events that are activated in response to a variety of extracellular stimuli such as stress factors, apoptosis, and proliferation. (aspetjournals.org)
  • A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). (wikipedia.org)
  • citation needed] MAPKs belong to the CMGC (CDK/MAPK/GSK3/CLK) kinase group. (wikipedia.org)
  • Because MAP2 kinases display very little activity on substrates other than their cognate MAPK, classical MAPK pathways form multi-tiered, but relatively linear pathways. (wikipedia.org)
  • In comparison to the three-tiered classical MAPK pathways, some atypical MAP kinases appear to have a more ancient, two-tiered system. (wikipedia.org)
  • Since removal of either phosphate groups will greatly reduce MAPK activity, essentially abolishing signaling, some tyrosine phosphatases are also involved in inactivating MAP kinases (e.g. the phosphatases HePTP, STEP and PTPRR in mammals). (wikipedia.org)
  • cyclin-depende
  • Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. (aacrjournals.org)
  • Since their initial discovery in yeast ( 1 ) and the identification of a first homologue in man ( 2 ), cyclin-dependent kinases (CDK) have been the object of considerable work with the aim of understanding their regulatory mechanisms and functions in controlling the various steps of the cell division cycle ( 3 ). (aacrjournals.org)
  • The closest relatives of MAPKs are the cyclin-dependent kinases (CDKs). (wikipedia.org)
  • phosphatidylinositol 3-kina
  • We investigated the effect of 2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1 H -imidazo[4,5- c ]quinolin-1-yl]phenyl} propanenitrile (NVP-BEZ235) (Novartis, Basel Switzerland), a dual phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor currently being tested in phase I clinical trials, in radiosensitization. (aspetjournals.org)
  • Many growth stimuli, such as insulin-like growth factor-1 (IGF-1), can bind to membrane-bound receptors that activate phosphatidylinositol-3-kinase (PI3K) and subsequently Akt ( 10 , 12 ). (physiology.org)
  • Inhibits
  • Inhibits a range of other kinases (IC 50 values in μM shown in brackets) including: CKI (0.51) Aurora B (2.5) DYRK3 (3.2) SGK1( 2.7) BRSK2 (1.1) and Lck (2.5). (abcam.com)
  • Competitive and reversible monoamine oxidase inhibitor (MAOI) that reversibly inhibits MAO-A (monoamine oxidase A) but has no effect on MAO-B. (adipogen.com)
  • G-protein RhoE binds to the N-terminus of ROCK1 and inhibits its activity by preventing RhoA binding. (wikipedia.org)
  • These substrates, once phosphorylated, regulate actin filament organization and contractility as follows: Amount of actin filaments ROCK inhibits the depolymerization of actin filaments indirectly: ROCK phosphorylates and activates LIM kinase, which in turn phosphorylates ADF/cofilin, thereby inactivating its actin-depolymerization activity. (wikipedia.org)
  • It is also possible that phosphorylation of collapsin response mediator protein-2 (CRMP2) by ROCK inhibits CRPM2 function of promoting axon outgrowth, resulting in growth cone collapse. (wikipedia.org)
  • substrate
  • A phosphorylation state‐specific antibody recognizes Hsp27, a novel substrate of protein kinase D. J. Biol. (currentprotocols.com)
  • Determination of the specific substrate sequence motifs of protein kinase C isozymes. (currentprotocols.com)
  • Without ATP bound, these kinases are unable to catalyze the transfer of the γ-phosphate from ATP to the kinase's target substrate, and thus function is hindered. (wikipedia.org)
  • When a substrate such as GTP-bound RhoA binds to the Rho-binding region of the coiled-coil domain, the interactions between the N-terminus and the C-terminus are disrupted, thus activating the protein. (wikipedia.org)
  • Thus in both cases, ROCK activation by Rho induces the formation of actin stress fibers, actin filament bundles of opposing polarity, containing myosin II, tropomyosin, caldesmon and MLC-kinase, and consequently of focal contacts, which are immature integrin-based adhesion points with the extracellular substrate. (wikipedia.org)
  • 3. Other ROCK targets NHE1 (a sodium hydrogen exchanger, involved in focal adhesions and actin organisation) intermediate filament proteins: Vimentin, GFAP (glial fibrillaric acidic protein), NF-L (neurofilament L protein) F-actin binding proteins: Adducin, EF-1α (elongation factor, translation co-factor), MARCKS (myristylated alanine-rich C kinase substrate), Caponin (unknown function), and ERM (involved in linkage of the actin cytoskelton to the plasma membrane). (wikipedia.org)
  • The structures of some autophosphorylation complexes are known from crystals of protein kinases in which the phosphorylation site (Ser, Thr, or Tyr) of one monomer in the crystal is sitting in the active site of another monomer of the crystal in a manner similar to known peptide-substrate/kinase structures. (wikipedia.org)
  • apoptosis
  • P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. (wikipedia.org)
  • Cleavage of the C-terminal inhibitory domain by caspase-3 during apoptosis can also activate the kinase. (wikipedia.org)
  • The histone deacetylase inhibitors are a new class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. (wikipedia.org)
  • pathway
  • Activation of the Foxo pathway leads to expression of atrogene products Atrogin-1/MAFbx and MuRF-1, proteins that are integral to the development of muscle atrophy ( 5 , 19 , 26 ). (physiology.org)
  • Identification of the tuberous sclerosis complex‐2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3‐kinase/akt pathway. (currentprotocols.com)
  • Similar to the SAPK/JNK pathway, p38 MAP kinase is activated by a variety of cellular stresses including osmotic shock, inflammatory cytokines, lipopolysaccharides (LPS), Ultraviolet light, and growth factors. (wikipedia.org)
  • Janus kinase 3 inhibitors work by inhibiting the action of the enzyme Janus Kinase 3 and therefore interferes with the JAK-STAT signaling pathway. (wikipedia.org)
  • signaling molecules
  • New forms of resistance can arise as: missense mutations within the Abl kinase domain, over-expression of Bcr-Abl, increased production of transmembrane plasma proteins, or the constitutive activation of downstream signaling molecules such as Src-family kinases. (wikipedia.org)
  • cellular
  • Identification of JAK3 inhibitor VI as a compound that efficiently abrogates ErbB2‐induced cellular invasion. (pubmedcentralcanada.ca)
  • For instance, the X-ray crystal structure of balanol in complex with PKA was used in order to confer selectivity and to improve pharmacological efficacy of inhibitors of the H. sapiens Akt (PKB), another serine/threonine protein kinase implicated in the proper functioning of many cellular processes. (wikipedia.org)
  • Cellular growth and reproduction may rely to some degree on tyrosine kinase. (wikipedia.org)
  • Furthermore, tyrosine kinase activity has been determined to be correlated to cellular transformation. (wikipedia.org)
  • A protein tyrosine kinase called pp125 is likely at hand in the influence of cellular focal adhesions, as indicated by an immunofluorescent localization of the said kinase. (wikipedia.org)
  • This tandem activation loop phosphorylation (that was proposed to be either distributive or processive, dependent on cellular environment) is performed by members of the Ste7 protein kinase family, also known as MAP2 kinases. (wikipedia.org)
  • An example of this is Decernotinib which showed 41-fold selectivity for JAK3 vs JAK1 in vitro enzyme assays while the selectivity for JAK3 was not maintained in cellular assays where it showed a slight preference for JAK1. (wikipedia.org)
  • ROCK plays a role in a wide range of different cellular phenomena, as ROCK is a downstream effector protein of the small GTPase Rho, which is one of the major regulators of the cytoskeleton. (wikipedia.org)
  • More specifically, Aurora kinases play a crucial role in cellular division by controlling chromatid segregation. (wikipedia.org)
  • binds
  • Since then crystallographic studies have revealed that imatinib binds to the kinase domain of Abl only when the domain adopts the inactive or "closed" conformation. (wikipedia.org)
  • regulators
  • Identification of lapatinib and JAK3 inhibitor VI as regulators of lysosome trafficking. (pubmedcentralcanada.ca)
  • Thus the role of mammalian ERK1/2 kinases as regulators of cell proliferation is not a generic, but a highly specialized function. (wikipedia.org)
  • Besides being implicated as mitotic regulators, these three kinases have generated significant interest in the cancer research field due to their elevated expression profiles in many human cancers. (wikipedia.org)
  • subunit
  • I KACh is a heterotetrameric G-protein coupled inward rectifying K + channel (GIRK) composed of (GIRK1) 2 /(GIRK4) 2 subunits, activated in response to the binding of the βγ-subunit of the heterotrimeric G-protein, G i2 , which is released after the binding of ACh to the M 2 muscarinic receptor ( 7 , 8 ). (diabetesjournals.org)
  • imatinib
  • Due to increasing resistance and intolerance to imatinib efforts were made to develop new drugs that could inhibit the Bcr-Abl tyrosine kinase. (wikipedia.org)
  • While drug screening was used to develop imatinib, second generation TKI's were developed with rational drug design approach due to increased knowledge in structural biology of the Bcr-Abl tyrosine kinase. (wikipedia.org)
  • Imatinib (Gleevec) was discovered in 1992 and is regarded as first generation drug since it is the first Bcr-Abl tyrosine kinase inhibitor to be used in the treatment of CML. (wikipedia.org)
  • In the development of imatinib, the structure of Bcr-Abl tyrosine kinase played a limited role because it was unknown. (wikipedia.org)
  • At the time of its discovery, in the absence of structural information, no clear explanation for the impressive selectivity of imatinib could be found. (wikipedia.org)
  • CDKs
  • Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine ( R )-roscovitine (CYC202/Seliciclib). (aacrjournals.org)
  • CDKs have also been the targets of numerous molecular screening studies designed to identify low molecular weight pharmacologic inhibitors with potential use against various human diseases derived from abnormal cell cycle regulation (review in ref. 4 ). (aacrjournals.org)
  • MAPKs
  • In contrast to the classical MAP kinases, these atypical MAPKs require only a single residue in their activation loops to be phosphorylated. (wikipedia.org)
  • As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above the actual MAP kinase. (wikipedia.org)
  • structurally
  • In particular, one class of p38 MAP kinase inhibitors, the pyridinyl imidazole derivatives, is intensely investigated by several industrial groups, but so far no studies concerning the metabolism of these structurally related substances seem to be available. (aspetjournals.org)
  • novel
  • Our results further showed that JAK3 inhibitor VI function was independent of JAK kinases but involved downregulation of cathepsin L. We postulate that the screening method and the verification experiments that are based on oncogene‐induced changes in lysosomal hydrolase activity and lysosomal distribution could be used for identification of novel inhibitors of ErbB2‐induced invasiveness. (pubmedcentralcanada.ca)
  • Staurosporine is the precursor of the novel protein kinase inhibitor midostaurin (PKC412). (wikipedia.org)
  • GSK3
  • Treatment of atrial myocytes with the GSK3β inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and I KACh , whereas a dominant-active GSK3β mutant decreased SREBP-1 and GIRK4 expression. (diabetesjournals.org)
  • In Akita mice treated with GSK3β inhibitors Li + and/or CHIR-99021, Li + increased I KACh , and Li + and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. (diabetesjournals.org)
  • isoforms
  • Similar regulation of human inducible nitric-oxide synthase expression by different isoforms of the RNA-binding protein AUF1," The Journal of Biological Chemistry , vol. 284, no. 5, pp. 2755-2766, 2009. (hindawi.com)
  • It is thought to be likely that the unique N-terminal or C-terminal regions of the various isoforms allow the different proteins to be targeted to specific subcellular domains. (wikipedia.org)
  • staurosporine
  • Does anyone have any experience using PKC inhibitors (e.g., staurosporine, calphostin C, HA-1077) or protein phosphatase inhibitors (e.g., okadaic acid, calyculin A) on C. elegans in vivo? (bio.net)
  • Structural analysis of kinase pockets demonstrated that main chain atoms which are conserved in their relative positions to staurosporine contributes to staurosporine promiscuity. (wikipedia.org)
  • human cancers
  • Amongst his most significant scientific achievements to date are the elucidation of basic regulatory mechanisms of tyrosine kinases in human cancers, the identification of the molecular mechanisms of several drugs, and the discovery of fundamental organization principles of the proteome and the lipidome of higher organisms, as well as the characterization of molecular components relevant for innate immunity. (wikipedia.org)
  • Thus
  • ERK3 (MAPK6) and ERK4 (MAPK4) were recently shown to be directly phosphorylated and thus activated by PAK kinases (related to other MAP3 kinases). (wikipedia.org)
  • Dehydrons cause "epistructural tension", that is, interfacial tension around the protein structure and thus promote protein-protein interactions and protein-ligand associations. (wikipedia.org)
  • Thus, dehydrons constitute effective selectivity filters for drug design, giving rise to so-called "wrapping technology", a platform to design safer drugs. (wikipedia.org)
  • clinical
  • Our data offer a rationale for combining NVP-BEZ235 along with an autophagy inhibitor (i.e., chloroquine) and radiation in future clinical trials. (aspetjournals.org)
  • Clinical trials in humans began in 2010, making CK-4945 the first CK2 inhibitor to reach this stage of drug development. (wikipedia.org)