Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A PCR approach has been employed to screen two cDNA libraries for PKC(-related) sequences. In each case multiple cDNAs were identified, including known PKC isotypes, a previously unknown PKC-eta related sequence and three members of what appears to be a protein kinase C related kinase (PRK 1-3) family. The origin and relationships of these predicted proteins is discussed.
 ...
PMID:Identification of multiple, novel, protein kinase C-related gene products. 798 19

The 80kDa Myristolated Alanine-Rich C-Kinase Substrate (MARCKS) is a major in vivo substrate of protein kinase C (PKC). Here we report that MARCKS is a major substrate for the lipid-activated PKC-related kinase (PRK1) in cell extracts. Furthermore, PRK1 is shown to phosphorylate MARCKS on the same sites as PKC in vitro. Thus, control of MARCKS phosphorylation on these previously identified 'PKC' sites may be regulated under certain circumstances by PRK as well as PKC mediated signalling pathways. The implications for MARCKS as a marker of PKC activation and as a point of signal convergence are discussed.
 ...
PMID:PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. 855 18

In eukaryotes, the Rho GTPases and their effectors are key regulators of the actin cytoskeleton, membrane trafficking and secretion, cell growth, cell cycle progression and cytokinesis. Budding yeast Pkc1p, a protein kinase C-like enzyme involved in cell wall biosynthesis and cytoskeletal polarity, is structurally and functionally related to the Rho-associated kinases (PRK/ROCK) of mammalian cells. In this study, localization of Pkc1p was monitored in live cells using a GFP fusion (Pkc1p-GFP). Pkc1p-GFP showed dynamic spatial and temporal localization at sites of polarized growth. Early in the cell cycle, Pkc1p-GFP was found at the pre-bud site and bud tips, becoming delocalized as the cell progressed further and finally relocalizing around the mother-daughter bud neck in an incomplete ring, which persisted until cell separation. Bud localization was actin-dependent but stability of Pkc1p-GFP at the neck was actin-independent, although localization at both sites required functional Rho1p. In addition, Pkc1p-GFP showed rapid relocalization after cell wall damage. These results suggest that the roles of Pkc1p in both polarized growth and the response to cell wall stress are mediated by dynamic changes in its localization, and suggest an additional potential role in cytokinesis.
 ...
PMID:Dynamic, Rho1p-dependent localization of Pkc1p to sites of polarized growth. 1089 84

Two new serine/threonine protein kinases have been cloned from Hydra cDNA. The first of these kinases belongs to the PKB/Akt family. It is expressed ubiquitously in Hydra at a relatively low level but is upregulated during head regeneration. The second kinase is a member of the PRK/PKN family. It is ubiquitously expressed in Hydra tissue, albeit at a higher level than PKB. Construction of a phylogenetic tree including the Hydra PRK and PKB kinases and two PKC homologs previously cloned by Hassel and comparing them with members of the PKC, PKB and PRK families from porifera, Dictyostelium,yeast, Drosophila, Caenorhabditis and humans provide support for a simple model for the evolution of these kinase families. An ancestral precursor which contained a pleckstrin homology domain in its N-terminus and a C-terminal kinase domain gave rise to PKB in Dictyostelium. From this ancestor the PKB/PRK and PKC families evolved. The pleckstrin homology domain was lost in the PKC and PRK families and kept in the PKB family. PKB homologs have now been found in a variety of multicellular animals with Hydra being the phylogenetically earliest representative. Members of the PRK/PKC family, on the other hand, are also present in fungi. The precursor for these kinases must have contained N-terminal regulatory domains that were retained in fungal PRKs but subsequently partitioned between kinases of the PKC and PRK groups in metazoans.
 ...
PMID:Cloning and characterisation of PKB and PRK homologs from Hydra and the evolution of the protein kinase family. 1245 19

In addition to the classical activation by ligands, nuclear receptor activity is also regulated by ligand-independent signalling. Here, we unravel a novel signal transduction pathway that links the RhoA effector protein kinase C-related kinase PRK1 to the transcriptional activation of the androgen receptor (AR). Stimulation of the PRK signalling cascade results in a ligand-dependent superactivation of AR. We show that AR and PRK1 interact both in vivo and in vitro. The transactivation unit 5 (TAU-5) located in the N-terminus of AR suffices for activation by PRK1. Thus, TAU-5 defines a novel, signal-inducible transactivation domain. Furthermore, PRK1 promotes a functional complex of AR with the co-activator TIF-2. Importantly, PRK signalling also stimulates AR activity in the presence of adrenal androgens, which are still present in prostate tumour patients subjected to testicular androgen ablation therapy. Moreover, PRK1 activates AR even in the presence of the AR antagonist cyproterone acetate that is used in the clinical management of prostate cancer. Since prostate tumours strongly overexpress PRK1, our data support a model in which AR activity is controlled by PRK signalling.
 ...
PMID:A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer. 1251 33

PKN is a serine/threonine protein kinase that has a catalytic domain homologous to protein kinase C (PKC) family members and a unique regulatory region containing antiparallel coiled-coil (ACC) domains. PKN is the first identified serine/threonine protein kinase that can bind to and be activated by a small GTPase Rho, and it can also be activated by fatty acids such as arachidonic acid in vitro. PKN is widely distributed in various organisms such as mammal, frog, fly, and starfish. There are at least three different isoforms of PKN (PKNalpha/PAK-1/PRK-1, PKNbeta, and PRK2/PAK-2/PKNgamma) in mammals, each of which shows different enzymological properties, tissue distribution, and varied functions.
 ...
PMID:The structure and function of PKN, a protein kinase having a catalytic domain homologous to that of PKC. 1276 Nov 94

The growth factor/insulin-stimulated AGC kinases share an activation mechanism based on three phosphorylation sites. Of these, only the role of the activation loop phosphate in the kinase domain and the hydrophobic motif (HM) phosphate in a C-terminal tail region are well characterized. We investigated the role of the third, so-called turn motif phosphate, also located in the tail, in the AGC kinases PKB, S6K, RSK, MSK, PRK and PKC. We report cooperative action of the HM phosphate and the turn motif phosphate, because it binds a phosphoSer/Thr-binding site above the glycine-rich loop within the kinase domain, promoting zipper-like association of the tail with the kinase domain, serving to stabilize the HM in its kinase-activating binding site. We present a molecular model for allosteric activation of AGC kinases by the turn motif phosphate via HM-mediated stabilization of the alphaC helix. In S6K and MSK, the turn motif phosphate thereby also protects the HM from dephosphorylation. Our results suggest that the mechanism described is a key feature in activation of upto 26 human AGC kinases.
 ...
PMID:Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation. 1744 65

PKN (protein kinase N; also called protein kinase C-related kinase (PRK-1)), is a serine/threonine protein kinase that is ubiquitously expressed in several organs, including the brain. PKN has a molecular mass of 120 kDa and has two domains, a regulatory and a catalytic domain, in its amino-terminals and carboxyl-terminus, respectively. Although the role of PKN has not been fully elucidated, previous studies have revealed that PKN is cleaved to a constitutively active catalytic fragment of 55 kDa in response to apoptotic signals. Hydrocephalus is a pathological condition caused by insufficient cerebrospinal fluid (CSF) circulation and subsequent excess of CSF in the brain. In this study, in order to elucidate the role of PKN in the pathophysiology of hydrocephalus, we examined PKN fragmentation in hydrocephalic model rats. Hydrocephalus was induced in rats by injecting kaolin into the cisterna magna. Kaolin-induced rats (n=60) were divided into three groups according to the observation period after treatment (group 1: 3-6 weeks, group 2: 7-12 weeks, and group 3: 13-18 weeks). Sham-treated control rats, injected with sterile saline (n=20), were similarly divided into three groups. Spatial learning ability was estimated by a modified water maze test. Thereafter, brains were cut into slices and ventricular dilatation was estimated. Fragmentation of PKN was observed by Western blotting in samples collected from the parietal cortex, striatum, septal nucleus, hippocampus, and periaqueductal gray matter. All kaolin-induced rats showed ventricular dilatation. Most of them showed less spatial learning ability than those of sham-treated controls. In most regions, fragmentation of PKN had occurred in a biphasic manner more frequently than that in controls. The appearance of PKN fragmentation in periaqueductal gray matter was correlated with the extent of ventricular dilation and spatial learning disability. These results revealed that PKN fragmentation was observed in rats with kaolin-induced hydrocephalus, models for chronically-damaged brain dysfunction, suggesting that persistent brain insult, such as apoptosis, had occurred in these models. PKN fragmentation could be a hallmark for evaluating morphological and functional damage of the hydrocephalus.
 ...
PMID:Fragmentation of protein kinase N (PKN) in the hydrocephalic rat brain. 1789 75

Class IIa histone deacetylases (HDACs) -4, -5, -7 and -9 undergo signal-dependent nuclear export upon phosphorylation of conserved serine residues that are targets for 14-3-3 binding. Little is known of other mechanisms for regulating the subcellular distribution of class IIa HDACs. Using a biochemical purification strategy, we identified protein kinase C-related kinase-2 (PRK2) as an HDAC5-interacting protein. PRK2 and the related kinase, PRK1, phosphorylate HDAC5 at a threonine residue (Thr-292) positioned within the nuclear localization signal (NLS) of the protein. HDAC7 and HDAC9 contain analogous sites that are phosphorylated by PRK, while HDAC4 harbors a non-phosphorylatable alanine residue at this position. We provide evidence to suggest that the unique phospho-acceptor cooperates with the 14-3-3 target sites to impair HDAC nuclear import.
 ...
PMID:Protein kinase C-related kinase targets nuclear localization signals in a subset of class IIa histone deacetylases. 2018 95

The group of AGC protein kinases includes more than 60 protein kinases in the human genome, classified into 14 families: PDK1, AKT/PKB, SGK, PKA, PKG, PKC, PKN/PRK, RSK, NDR, MAST, YANK, DMPK, GRK and SGK494. This group is also widely represented in other eukaryotes, including causative organisms of human infectious diseases. AGC kinases are involved in diverse cellular functions and are potential targets for the treatment of human diseases such as cancer, diabetes, obesity, neurological disorders, inflammation and viral infections. Small molecule inhibitors of AGC kinases may also have potential as novel therapeutic approaches against infectious organisms. Fundamental in the regulation of many AGC kinases is a regulatory site termed the "PIF-pocket" that serves as a docking site for substrates of PDK1. This site is also essential to the mechanism of activation of AGC kinases by phosphorylation and is involved in the allosteric regulation of N-terminal domains of several AGC kinases, such as PKN/PRKs and atypical PKCs. In addition, the C-terminal tail and its interaction with the PIF-pocket are involved in the dimerization of the DMPK family of kinases and may explain the molecular mechanism of allosteric activation of GRKs by GPCR substrates. In this review, we briefly introduce the AGC kinases and their known roles in physiology and disease and the discovery of the PIF-pocket as a regulatory site in AGC kinases. Finally, we summarize the current status and future therapeutic potential of small molecules directed to the PIF-pocket; these molecules can allosterically activate or inhibit the kinase as well as act as substrate-selective inhibitors. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
 ...
PMID:AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases. 2352 93


1 2 Next >>