Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-Jun N-terminal kinases (JNKs) are activated in response to stress, DNA damage, and cytokines by MKK4 and MKK7. We recently demonstrated that PKC can augment the degree of JNK activation by phosphorylating JNK, which requires the adaptor protein RACK1. Here we report on the conditions required for PKC-dependent JNK activation. In vitro kinase assays reveal that PKC phosphorylation of JNK is not sufficient for its activation but rather augments JNK activation by canonical JNK upstream kinases MKK4 or MKK7 alone or in combination. Further, to enhance JNK activity, PKC phosphorylation of JNK should precede its phosphorylation by MKK4/7. Inhibition of PKC phosphorylation of JNK affects both early and late phases of JNK activation following UV-irradiation and reduces the apoptotic response mediated by JNK. These data provide important insight into the requirements for PKC activation of JNK signaling.
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PMID:Requirements for PKC-augmented JNK activation by MKK4/7. 1818 17

Surface plasmon resonance (SPR) biosensors detect large changes of angle of resonance (AR) when RBL-2H3 mast cells are cultured on a sensor chip and stimulated with antigen. However, the detail of molecular events that are responsible for such large changes of AR remained unknown. In this study, we investigated the relationship between intracellular signaling events induced by antigen and the change of AR, by genetic manipulation of intracellular signaling molecules; spleen tyrosine kinase (Syk), src-like adaptor protein (SLAP), linker for activation of T cells (LAT), growth-factor-receptor-bound protein 2 (Grb2), Grb2-related adaptor protein (Gads), and isotypes of protein kinase C (PKC). RBL-2H3 mast cells overexpressing dominant-negative Syk or SLAP, which both interfere with active Syk, exhibited only minimal increase of AR in response to antigen stimulation. Likewise, the interference of the activation of LAT and Gads, by expressing dominant-negative LAT and Gads, respectively, resulted in nearly complete suppression of the antigen-induced increase of AR. The cells overexpressing PKCs, apart from PKCbeta, showed a reduced extent of increase of AR in response to antigen stimulation. Moreover, the introduction of the small interfering RNA targeted against PKCbeta suppressed the antigen-induced increase of AR. These results indicate that the activation of Syk, LAT, Gads, and subsequent PKCbeta is indispensable for the antigen-induced increase of AR of mast cells detected by SPR biosensors.
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PMID:Surface plasmon resonance biosensor detects the downstream events of active PKCbeta in antigen-stimulated mast cells. 1833 33

A number of studies support the notion that lithium interacts with the protein kinase C (PKC) pathway, an important mediator of several intracellular responses to neurotransmitter signaling. PDLIM5 (PDZ and LIM domain 5; LIM) is an adaptor protein that selectively binds the isozyme PKC(epsilon) to N-type Ca(2+) channels in neurons. We tested for an association between three single nucleotide polymorphisms (SNPs) at the PDLIM5 gene and lithium prophylaxis in a Sardinian sample comprised of 155 bipolar patients treated with lithium. In order to evaluate whether PDLIM5 expression interacts with lithium response, we carried out gene expression analysis in lymphoblastoid cells of 30 bipolar patients. No association was shown between PDLIM5 polymorphisms and lithium response. When PDLIM5 expression was evaluated, no significant differences were detected between Full Responders to lithium (total score>or=7) and other patients (total score<or=6). Our negative findings do not exclude involvement of PDLIM5 in lithium prophylaxis, and further investigation is warranted.
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PMID:The PDLIM5 gene and lithium prophylaxis: an association and gene expression analysis in Sardinian patients with bipolar disorder. 1845 8

Endocytic processes are mediated by multiple protein-protein interacting modules and regulated by phosphorylation and dephosphorylation. The Eps15 homology domain containing protein 1 (EHD1) has been implicated in regulating recycling of proteins, internalized both in clathrin-dependent and clathrin-independent endocytic pathways, from the recycling compartment to the plasma membrane. EHD1 was found in a complex with clathrin, adaptor protein complex-2 (AP-2) and insulin-like growth factor-1 receptor (IGF-1R), and was shown to interact with Rabenosyn-5, SNAP29, EHBP1 (EH domain binding protein 1) and syndapin I and II. In this study, we show that EHD1, like the other human EHDs, undergoes serine-phosphorylation. Our results also indicate that EHD1 is a serum-inducible serine-phosphoprotein and that PKC (protein kinase C) is one of its kinases. In addition, we show that inhibitors of clathrin-mediated endocytosis decrease EHD1 phosphorylation, while inhibitors of caveolinmediated endocytosis do not affect EHD1 phosphorylation. The results of experiments in which inhibitors of endocytosis were employed strongly suggest that EHD1 phosphorylation occurs between early endosomes and the endocytic recycling compartment.
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PMID:EHDS are serine phosphoproteins: EHD1 phosphorylation is enhanced by serum stimulation. 1866 Nov 12

Pre-B cell receptor (pre-BCR) signals promote pre-B cell differentiation, in which the adaptor protein B-cell linker (BLNK) plays a crucial role. However, the molecular pathways downstream of BLNK are currently unclear. Utilizing pre-B leukemia cell lines (BKO84 and others) derived from BLNK-deficient mice as in vitro models of the pre-B cell differentiation, we have demonstrated that reconstitution of BLNK as well as an active form of protein kinase C (PKC)eta induces the differentiation events, such as pre-BCR down-regulation and kappa gene rearrangement. Here we show that the same events are induced by cross-linking of pre-BCR with anti-mu antibody in these pre-B cell lines, as well as in ex vivo pre-B cells from BLNK-deficient mice, suggesting a function of BLNK as an internal cross-linker of pre-BCR. Anti-mu treatment of BKO84 cells up-regulated membrane recruitment of PKC eta and the expression of IRF-4, a transcription factor known to promote light chain gene rearrangements. Anti-mu induction of surface kappa chain on BKO84 cells was blocked by reagents that inhibit phospholipase C or PKC. Enforced expression of the active PKC eta in BKO84 cells resulted in up-regulation of IRF-4 expression. Conversely, siRNA-mediated silencing of PKC eta expression strikingly attenuated the anti-mu-induced IRF-4 expression and kappa gene rearrangement, which were restored by PKC eta reconstitution. Finally, enforced expression of IRF-4, but not of BLNK, in the PKC eta-silenced BKO84 cells resulted in kappa gene rearrangement. These results indicate that PKC eta directs the induction of IRF-4 expression downstream of BLNK in the pre-BCR signaling pathway promoting kappa gene rearrangement.
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PMID:PKC eta directs induction of IRF-4 expression and Ig kappa gene rearrangement in pre-BCR signaling pathway. 1878 Jul 22

In response to an increased hemodynamic load, such as pressure or volume overload, cardiac hypertrophy ensues as an adaptive mechanism. Although hypertrophy initially maintains ventricular function, a yet undefined derailment in this process eventually leads to compromised function (decompensation) and eventually culminates in congestive heart failure (CHF). Therefore, determining the molecular signatures induced during compensatory growth is important to delineate specific mechanisms responsible for the transition into CHF. Compensatory growth involves multiple processes. At the cardiomyocyte level, one major event is increased protein turnover where enhanced protein synthesis is accompanied by increased removal of deleterious proteins. Many pathways that mediate protein turnover depend on a key molecule, mammalian target of rapamycin (mTOR). In pressure-overloaded myocardium, adrenergic receptors, growth factor receptors, and integrins are known to activate mTOR in a PI3K-dependent and/or independent manner with the involvement of specific PKC isoforms. mTOR, described as a sensor of a cell's nutrition and energy status, is uniquely positioned to activate pathways that regulate translation, cell size, and the ubiquitin-proteasome system (UPS) through rapamycin-sensitive and -insensitive signaling modules. The rapamycin-sensitive complex, known as mTOR complex 1 (mTORC1), consists of mTOR, rapamycin-sensitive adaptor protein of mTOR (Raptor) and mLST8 and promotes protein translation and cell size via molecules such as S6K1. The rapamycin-insensitive complex (mTORC2) consists of mTOR, mLST8, rapamycin-insensitive companion of mTOR (Rictor), mSin1 and Protor. mTORC2 regulates the actin cytoskeleton in addition to activating Akt (Protein kinase B) for the subsequent removal of proapoptotic factors via the UPS for cell survival. In this review, we discuss pathways and key targets of mTOR complexes that mediate growth and survival of hypertrophying cardiomyocytes and the therapeutic potential of mTOR inhibitor, rapamycin.
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PMID:mTOR in growth and protection of hypertrophying myocardium. 1914 44

Protein kinase C (PKC)epsilon overexpression in FVB/N transgenic mice sensitized skin to UVR-induced development of squamous cell carcinomas and suppressed formation of sunburn cells, which are DNA-damaged keratinocytes undergoing apoptosis. Here, we elucidated the mechanisms associated with the inhibition of UVR-induced appearance of sunburn cells in PKCepsilon transgenic mice. We found that the inhibition of UVR-induced sunburn cell formation in PKCepsilon transgenic mice may be the result of the inhibition of the expression of Fas, Fas ligand, and the mammalian death adaptor protein termed Fas-associated with death domain (FADD). The adaptor protein FADD is the key component of the death-inducing signaling complex of both Fas and tumor necrosis factor receptor 1. A decreased expression of epidermal FADD was observed after a single UVR exposure. However, a complete loss of FADD expression was found after four (Monday, Wednesday, Friday, and Monday) repeated UVR exposures. FADD transmits apoptotic signals from death receptors to the downstream initiator caspase-8 and connects to the mitochondrial intrinsic apoptotic signal transduction pathway by the cleavage of Bid, a Bcl-2 family member. PKCepsilon-mediated loss of FADD expression inhibited UVR signals to the activation of both extrinsic and intrinsic apoptotic pathways.
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PMID:Protein kinase Cepsilon inhibits UVR-induced expression of FADD, an adaptor protein, linked to both Fas- and TNFR1-mediated apoptosis. 1960 51

The delta-isozyme (type II) of diacylglycerol kinase (DGK) is known to positively regulate growth factor receptor signaling. DGKdelta, which is distributed to clathrin-coated vesicles, interacts with DGKdelta itself, protein kinase C and AP2alpha. To search for additional DGKdelta-interacting proteins, we screened a yeast two-hybrid cDNA library from HepG2 cells using aa 896-1097 of DGKdelta as a bait. We identified aa 184-317 (WD40 repeats 5-7) of receptor for activated C kinase 1 (RACK1), which interacts with various important signaling molecules, as a novel binding partner of DGKdelta. Co-immunoprecipitation analysis, using COS-7 cells co-expressing RACK1 and DGKdelta, revealed that RACK1 selectively interacted with DGKdelta, but not with type I DGKs, in mammalian cells. The interaction was dynamically regulated by phorbol ester. Intriguingly, DGKdelta appeared to recruit RACK1 to clathrin-coated vesicles and co-localized with RACK1. These results suggest that DGKdelta serves as an adaptor protein to regulate the localization of the versatile scaffold protein, RACK1.
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PMID:Diacylglycerol kinase delta associates with receptor for activated C kinase 1, RACK1. 1941 40

Activation of the NF-kappaB pathway in T cells is required for induction of an adaptive immune response. Hematopoietic progenitor kinase (HPK1) is an important proximal mediator of T-cell receptor (TCR)-induced NF-kappaB activation. Knock-down of HPK1 abrogates TCR-induced IKKbeta and NF-kappaB activation, whereas active HPK1 leads to increased IKKbeta activity in T cells. Yet, the precise molecular mechanism of this process remains elusive. Here, we show that HPK1-mediated NF-kappaB activation is dependent on the adaptor protein CARMA1. HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. In addition, CARMA1 S551A or S5549A/S551A point mutants failed to restore HPK1-mediated and TCR-mediated NF-kappaB activation and IL-2 expression in CARMA1-deficient T cells. Thus, we identify HPK1 as a kinase specific for CARMA1 and suggest HPK1-mediated phosphorylation of CARMA1 as an additional regulatory mechanism tuning the NF-kappaB response upon TCR stimulation.
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PMID:Phosphorylation of CARMA1 by HPK1 is critical for NF-kappaB activation in T cells. 1970 36

Integrins link the cytoskeleton to the extracellular matrix, providing outside-in/inside-out signalling essential for vascular smooth muscle cell (VSMC) migration in atherosclerosis. The integrin av subunit is synthesised from its precursor via furin-dependent endoproteolytic cleavage. Furin is a proprotein convertase (PC) highly expressed in VSMCs and in human atherosclerotic lesions. Inhibition of av processing inhibits binding to vitronectin and migration. However, the precise role of furin-dependent av cleavage on integrin bidirectional signalling and subsequent VSMC functions is unknown. Our present study demonstrates that the furin-like PC inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) inhibited av cleavage. This reduced vitronectin-induced (outside-in) focal adhesion kinase (FAK)- and paxillin-phosphorylation, and VSMC motility. Inside-out-stimulated, integrin- mediated VSMC adhesion/migration relied on integrin-adaptor protein activation following protein kinase C (PKC) and ERK1/2 phosphorylation. In contrast to outside-in signalling, PKC-dependent phosphorylation of FAK and paxillin was unaffected by the status of integrin cleavage. Still, cytoskeleton and focal adhesion site rearrangements were modulated by the inhibition of furin-dependent integrin cleavage, thereby lessening inside-out dependent migration. Hence, we find that integrin bidirectional signalling is critically controlled by furin. Furin- dependent integrin processing modulates rapid adaptive integrin/cytoskeleton changes, essential to VSMC motility, which represents a crucial component in atherosclerosis and restenosis.
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PMID:Integrin cleavage regulates bidirectional signalling in vascular smooth muscle cells. 2007 49


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