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 LIM domain is a specialized double-zinc finger motif found in a variety of proteins. LIM domains are thought to function as molecular modules, mediating specific protein-protein interactions in cellular signaling. In a recent study, we have demonstrated that ENH, which has three consecutive LIM domains, acts as an adaptor protein for the formation of a functional PKCepsilon-ENH-N-type Ca2+ channel complex in neurons. Formation of this complex selectively recruits PKCepsilon to its specific substrate, N-type Ca2+ channels, and is critical for rapid and efficient potentiation of the Ca2+ channel activity by PKC in neurons. However, it is not clear whether changes in the local Ca2+ concentrations near the channel mouth may affect the formation of the triprotein complex. Furthermore, the molecular determinants for the interactions among these three proteins remain unknown. Biochemical studies were performed to address these questions. Within the physiological Ca2+ concentration range (0-300 microM), binding of ENH to the channel C-terminus was significantly increased by Ca2+, whereas increased Ca2+ levels led to dissociation of PKCepsilon from ENH. Mutagenesis studies revealed that the second LIM domain in ENH was primarily responsible for Ca2+-dependent binding of ENH to both the Ca2+ channel C-terminus and PKCepsilon. ENH existed as a dimer in vivo. PKCepsilon translocation inhibition peptide, which blocks the translocation of PKCepsilon from the cytosol to the membrane, inhibited the interaction between PKCepsilon and ENH. These results provide a molecular mechanism for how the PKCepsilon-ENH-N-type Ca2+ channel complex is formed and regulated, as well as potential drug targets to selectively disrupt the PKC signaling complex.
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PMID:Essential role of the LIM domain in the formation of the PKCepsilon-ENH-N-type Ca2+ channel complex. 1597 48

Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular protons. The ASIC3 subunit is largely expressed in the peripheral nervous system, where it contributes to pain perception and to some aspects of mechanosensation. We report here a PDZ-dependent and protein kinase C-modulated association between ASIC3 and the Na+/H+ exchanger regulatory factor-1 (NHERF-1) adaptor protein. We show that NHERF-1 and ASIC3 are co-expressed in dorsal root ganglion neurons. NHERF-1 enhances the ASIC3 peak current in heterologous cells, including F-11 dorsal root ganglion cells, by increasing the amount of channel at the plasma membrane. Perhaps more importantly, we show that the plateau current of ASIC3 can be dramatically increased (10-30-fold) by association with NHERF-1, leading to a significant sustained current at pH 6.6. In the presence of NHERF-1, the ASIC3 subcellular localization is modified, and the channel co-localizes with ezrin, a member of the ezrin-radixin-moesin family of actin-binding proteins, providing the first direct link between ASIC3 and the cortical cytoskeleton. Given the importance of the ASIC3 sustained current in nociceptor excitability, it is likely that NHERF-1 participates in channel functions associated with nociception and mechanosensation.
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PMID:Regulation of sensory neuron-specific acid-sensing ion channel 3 by the adaptor protein Na+/H+ exchanger regulatory factor-1. 1623 33

Calcium/phospholipid-regulated protein kinase C (PKC) signalling is known to be involved in cellular functions relevant to brain health and disease, including ion channel modulation, receptor regulation, neurotransmitter release, synaptic plasticity, and survival. Brain aging is characterized by altered neuronal molecular cascades and interneuronal communication in response to various stimuli. In the last few years we have provided evidence that in rodents, despite no changes in PKC isoform levels (both calcium dependent and calcium independent), the activation/translocation process of the calcium-dependent and -independent kinases and the content of the adaptor protein RACK1 (receptor for activated C kinase-1) are deficient in physiological brain aging. Moreover, human studies have shown that PKC and its adaptor protein RACK1 are also interdependent in pathological brain aging (e.g., Alzheimer's disease); in fact, calcium-dependent PKC translocation and RACK1 levels are both deficient in an area-selective manner. These data point to the notion that, in addition to a well-described lipid environment alteration, changes in protein-protein interactions may impair the mechanisms of PKC activation in aging. It is interesting to note that interventions to counteract the age-related functional loss also restore PKC activation and the adaptor protein machinery expression. A better insight into the factors controlling PKC activation may be important not only to elucidate the molecular basis of signal transmission, but also to identify new strategies to correct or even to prevent age-dependent alterations in cell-to-cell communication.
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PMID:Protein kinase C signal transduction regulation in physiological and pathological aging. 1639 94

Ki-1/57 is a cytoplasmic and nuclear phospho-protein of 57 kDa and interacts with the adaptor protein RACK1, the transcription factor MEF2C, and the chromatin remodeling factor CHD3, suggesting that it might be involved in the regulation of transcription. Here, we describe yeast two-hybrid studies that identified a total of 11 proteins interacting with Ki-1/57, all of which interact or are functionally associated with p53 or other members of the p53 family of proteins. We further found that Ki-1/57 is able to interact with p53 itself in the yeast two-hybrid system when the interaction was tested directly. This interaction could be confirmed by pull down assays with purified proteins in vitro and by reciprocal co-immunoprecipitation assays from the human Hodgkin analogous lymphoma cell line L540. Furthermore, we found that the phosphorylation of p53 by PKC abolishes its interaction with Ki-1/57 in vitro.
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PMID:Evidence for the interaction of the regulatory protein Ki-1/57 with p53 and its interacting proteins. 1645 55

The receptor for activated protein kinase C 1 (RACK1) is an intracellular adaptor protein. Accumulating evidence attributes to this member of the tryptophan-aspartate (WD) repeat family the role of regulating several major nervous system pathways. Structurally, RACK1 is a seven-bladed-beta-propeller, interacting with diverse proteins having distinct structural folds. When bound to the IP3 receptor, RACK1 regulates intracellular Ca2+ levels, potentially contributing to processes such as learning, memory and synaptic plasticity. By binding to the NMDA receptor, it dictates neuronal excitation and sensitivity to ethanol. When bound to the stress-induced acetylcholinesterase variant AChE-R, RACK1 is implicated in stress responses and behavior, compatible with reports of RACK1 modulations in brain ageing and in various neurodegenerative diseases. This review sheds new light on both the virtues and the variety of neuronal RACK1 interactions and their physiological consequences.
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PMID:RACK1 has the nerve to act: structure meets function in the nervous system. 1645 39

Activation of G protein-coupled receptor by dopamine and hypoxia-generated reactive oxygen species promote Na+,K+-ATPase endocytosis. This effect is clathrin dependent and involves the activation of protein kinase C (PKC)-zeta and phosphorylation of the Na+,K+-ATPase alpha-subunit. Because the incorporation of cargo into clathrin vesicles requires association with adaptor proteins, we studied whether phosphorylation of adaptor protein (AP)-2 plays a role in its binding to the Na+,K+-ATPase alpha-subunit and thereby in its endocytosis. Dopamine induces a time-dependent phosphorylation of the AP-2 mu2 subunit. Using specific inhibitors and dominant-negative mutants, we establish that this effect was mediated by activation of the adaptor associated kinase 1/PKC-zeta isoform. Expression of the AP-2 mu2 bearing a mutation in its phosphorylation site (T156A) prevented Na+,K+-ATPase endocytosis and changes in activity induced by dopamine. Similarly, in lung alveolar epithelial cells, hypoxia-induced endocytosis of Na+,K+-ATPase requires the binding of AP-2 to the tyrosine-based motif (Tyr-537) located in the Na+,K+-ATPase alpha-subunit, and this effect requires phosphorylation of the AP-2 mu2 subunit. We conclude that phosphorylation of AP-2 mu2 subunit is essential for Na+,K+-ATPase endocytosis in response to a variety of signals, such as dopamine or reactive oxygen species.
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PMID:Phosphorylation of adaptor protein-2 mu2 is essential for Na+,K+-ATPase endocytosis in response to either G protein-coupled receptor or reactive oxygen species. 1678 42

Protein kinase C (PKC) represents a large family of phosphatidylserine (PS)-dependent serine/threonine protein kinases. At least five PKC isoforms (alpha, delta, epsilon, eta, and zeta) are expressed in epidermal keratinocytes. PKC isoforms are differentially expressed in proliferative (basal layer) and nonproliferative compartments (spinous, granular, cornified layers), which exhibit divergence in their roles in the regulation of epidermal cell proliferation, differentiation, and apoptosis. Immunocytochemical localization of PKC isoforms indicate that PKCalpha is found in the membranes of suprabasal cells in the spinous and granular layers. PKCepsilon is mostly localized in the proliferative basal layers. PKCeta is localized exclusively in the granular layer. PKCdelta is detected throughout the epidermis. PKC isozymes exhibit specificities in their signals to the development of skin cancer. PKCepsilon, a calcium-insensitive PKC isoform mediates the induction of squamous cell carcinoma (SCC) elicited either by the DMBA-TPA protocol or by repeated exposures to ultraviolet radiation (UVR). PKCepsilon overexpression, which sensitizes skin to UVR-induced carcinogenesis, suppresses UVR-induced sunburn (apoptotic) cell formation, and enhances both UVR-induced levels of TNFalpha and hyperplasia. UVR-induced sunburn cell formation is mediated by Fas/Fas-L and TNFalpha NFR1 extrinsic apoptotic pathways. The death adaptor protein termed Fas-associated death domain (FADD) is a common adaptor protein for both of these apoptotic pathways. PKCepsilon inhibits UVR-induced expression of FADD leading to the inhibition of both apoptotic pathways. It appears that PKCepsilon sensitizes skin to the development of SCC by UVR by transducting signals, which inhibit apoptosis on one hand, and enhances proliferation of preneoplastic cells on the other hand.
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PMID:Protein kinase Cepsilon and development of squamous cell carcinoma, the nonmelanoma human skin cancer. 1668 53

Ki-1/57 is a 57-kDa cytoplasmic and nuclear protein associated with protein kinase activity and is hyper-phosphorylated on Ser/Thr residues upon cellular activation. In previous studies we identified the receptor of activated kinase-1 (RACK1), a signaling adaptor protein that binds activated PKC, as a protein that interacts with Ki-1/57. Here we demonstrate that the far-UV circular dichroism spectrum of the WD repeat-containing RACK1 protein shows an unusual positive ellipticity at 229 nm, which in other proteins of the WD family has been attributed to surface tryptophans that are quenchable by N-bromosuccinimide (NBS). As well as NBS, in vitro binding of 6xHis-Ki-1/57(122-413) and 6xHis-Ki-1/57(264-413) can also quench the positive ellipticity of the RACK1 spectrum. We generated a model of RACK1 by homology modeling using a G protein beta subunit as template. Our model suggests the family-typical seven-bladed beta-propeller, with an aromatic cluster around the central tunnel that contains four Trp residues (17, 83, 150, 170), which are likely involved in the interaction with Ki-1/57.
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PMID:A spectroscopic analysis of the interaction between the human regulatory proteins RACK1 and Ki-1/57. 1674 Jan 29

PER1, an important component of circadian clock systems, plays a critical role in regulating the period length and maintaining the precision and stability of the period of circadian rhythms. RACK1 (receptor for activated protein kinase C-1), a member of the WD-40 family of proteins, can interact with numerous signaling proteins and is regarded as a scaffolding, anchor, or adaptor protein in multiple intracellular signal transduction pathways. In the present study, we identified and confirmed RACK1 as a novel protein interacting with human clock protein, hPER1, using the yeast two-hybrid system and co-immunoprecipitation experiment. Further study by RT-PCR showed that RACK1 was expressed widely in tissues and there was no obvious expressional rhythmicity. However, RNA interfering plasmid inhibiting hPER1 (pTER/hPER1-II) could not interfere expression of RACK1. These results together suggested that RACK1 might act as a novel signal molecule to mediate or regulate the functions of PER1 through protein interaction.
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PMID:RACK1, a novel hPER1-interacting protein. 1675 10

The pre-B-cell receptor (pre-BCR) is thought to signal transcriptional activation of the immunoglobulin light (L) chain gene locus, proceeding to its V-J rearrangement. The pre-BCR signaling pathway for this process is largely unknown but may involve the adaptor protein BASH (BLNK/SLP-65). Here we report that the pre-B leukemia cell lines established from affected BASH-deficient mice rearrange kappaL-chain gene locus and down-regulate pre-BCR upon PMA treatment or BASH reconstitution. Analyses with specific inhibitors revealed that activation of novel PKC (nPKC) and MEK, but not Ras, is necessary for the rearrangement. Accordingly, retroviral transduction of active PKCeta, PKCepsilon, or Raf-1, but not Ras, induced the kappa gene rearrangement and expression in the pre-B-cell line. Tamoxifen-mediated BASH reconstitution resulted in the translocation of PKCeta to the plasma membrane and kappa chain expression. These data make evident that the Ras-independent BASH-nPKC-Raf-1 pathway of pre-BCR signaling induces the L-chain gene rearrangement and expression.
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PMID:BASH-novel PKC-Raf-1 pathway of pre-BCR signaling induces kappa gene rearrangement. 1679 53


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