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)

Based on the reports of the activation of the transcription factor known as STAT3 (for signal transducers and activators of transcription) or APRF (for acute phase response factor) by various cytokines, we investigated the possible role of STAT3 in type I interferon (IFN) receptor signaling. We show that STAT3 undergoes IFNalpha-dependent tyrosine phosphorylation and IFNalpha treatment induces protein-DNA complexes that contain STAT3. In addition, STAT3 associates with the IFNAR-1 chain of the type I receptor in a tyrosine phosphorylation-dependent manner upon IFNalpha addition. The binding of STAT3 to the IFNAR-1 chain occurs through a direct interaction between the SH2 domain-containing portion of STAT3 and the tyrosine-phosphorylated IFNAR-1 chain. Furthermore, tyrosine-phosphorylated STAT3 bound to the IFNAR-1 chain also undergoes a secondary modification involving serine phosphorylation. This phosphorylation event is apparently mediated by protein kinase C, since it was blocked by low concentrations of the protein kinase inhibitor H-7. The biological relevance of IFN activation of STAT3 is further illustrated by the finding that STAT3 is not activated by IFN in a cell line resistant to the antiviral and antiproliferative actions of IFN alpha but in which other components of the JAK-STAT pathway are activated by IFNalpha.
 ...
PMID:Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor. 862 89

We have examined the effects of l-thyroxine (T4) on the activation of signal transducer and activator of transcription 3 (STAT3) and on the STAT3-dependent induction of c-Fos expression by epidermal growth factor (EGF). T4, at a physiological concentration of 100 nM, caused tyrosine phosphorylation and nuclear translocation (i.e. activation) of STAT3 in HeLa cells in as little as 10-20 min. Activation by T4 of STAT3 was maximal at 30 min (15+/-4-fold enhancement; mean+/-S.E.M.) in 18 experiments. This effect was reproduced by T4-agarose (100 nM) and blocked by CGP 41251, genistein, PD 98059 and geldanamycin, inhibitors of protein kinase C (PKC), protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK) kinase and Raf-1 respectively. Tyrosine-phosphorylated MAPK also appeared in nuclear fractions within 10 min of treatment with T4. In the nuclear fraction of T4-treated cells, MAPK immunoprecipitate also contained STAT3. The actions of T4 were similar in HeLa and CV-1 cells, which lack thyroid hormone receptor (TR), and in TR-replete skin fibroblasts (BG-9). T4 also potentiated the EGF-induced nuclear translocation of activated STAT1alpha and STAT3 and enhanced the EGF-stimulated expression of c-Fos. Hormone potentiation of EGF-induced signal transduction and c-Fos expression was inhibited by CGP 41251, geldanamycin and PD 98059. Therefore the non-genomically induced activation by T4 of STAT3, and the potentiation of EGF by T4, require activities of PKC, PTK and an intact MAPK pathway.
 ...
PMID:Thyroid hormone promotes the phosphorylation of STAT3 and potentiates the action of epidermal growth factor in cultured cells. 1002 19

STAT3 (signal transducer and activator of transcription 3) is a latent transcription factor that is activated by tyrosine phosphorylation (Tyr-705) in cells stimulated with cytokines or growth factors. Recent studies suggest that one or more cytoplasmic serine kinases also phosphorylate STAT3 and are necessary for maximal gene activation. Here we demonstrate, with a site-specific antibody, that STAT3 is phosphorylated on Ser-727 in human neutrophils stimulated with chemotactic factors (N-formyl-methionyl-leucyl-phenylalanine and complement C5a), cytokines [granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF)], or a protein kinase C activator (PMA). (2-Amino-3'-methoxyphenyl)oxanaphthalen-4-one (PD 98059), an inhibitor of extracellular signal-regulated protein kinase (ERK) activation, blocked the serine phosphorylation of STAT3 induced by chemotactic factors or PMA. The drug was less effective on cytokines: it virtually abolished the response to GM-CSF that occurred 5 min after stimulation but only partly decreased those at 15-30 min and did not appreciably alter responses to G-CSF regardless of incubation time. 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride (H7), an inhibitor of a putative STAT3 serine kinase, and 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB 203580), an inhibitor of p38 mitogen-activated protein (MAP) kinase, did not dampen any of these serine phosphorylation responses. We propose that neutrophils use both ERK-dependent and ERK-independent pathways to phosphorylate Ser-727 on STAT3. The former pathway is recruited by all ERK-activating stimuli, whereas the latter pathway uses an undefined serine kinase and is recruited selectively by cytokines.
 ...
PMID:Extracellular signal-regulated protein kinase (ERK)-dependent and ERK-independent pathways target STAT3 on serine-727 in human neutrophils stimulated by chemotactic factors and cytokines. 1041 33

The hair follicle is an epidermal derivative that undergoes cycles of growth, involution, and rest. The hair cycle has well-orchestrated kinetics regulated by interactions between mesenchymal and epithelial cells, although the intracellular signals remain unclear. We previously established keratinocyte-specific Stat3-disrupted mice, by which we demonstrated that signal transducer and activator of transcription 3 (Stat3) is required for wound healing and anagen progression in the hair cycle. Growth factor-dependent migration of Stat3-disrupted keratinocytes was severely impaired, suggesting that not only wound healing but also telogen-to-anagen progression required organized keratinocyte migration in response to mesenchymal stimuli. In the present study, to examine whether Stat3 activation in keratinocytes is a prerequisite for hair cycle progression, we applied methods for experimental anagen induction to Stat3-disrupted mice. It was demonstrated that anagen was successfully induced in Stat3-disrupted as well as wild-type mice by chemical or mechanical stimulation, i.e. , by topical application of phorbol 12-myristate 13-acetate (PMA) or by hair plucking, respectively. This result indicated that anagen in these methods occurred in the absence of Stat3. Furthermore, PMA stimulated the migration of Stat3-disrupted keratinocytes in vitro, supporting a hypothesis that the protein kinase C (PKC) and Stat3 pathways occur independently in the postnatal anagen induction. Both Stat3-dependent and -independent migration of keratinocytes was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin. Therefore, we infer that entry into anagen is mediated by at least two distinct signaling pathways: Stat3-dependent pathway for spontaneous hair cycling and Stat3-independent (probably PKC-dependent) pathway for exogenously induced hair cycling, whereas both pathways require PI3K activation.
 ...
PMID:Two distinct signaling pathways in hair cycle induction: Stat3-dependent and -independent pathways. 2591 11

Monocyte chemotactic protein 1 (MCP-1), which is synthesized by vascular cells, is a chemoattractant for monocytes and has been implicated in a wide range of acute and chronic inflammatory processes characterized by monocyte infiltration, including atherosclerosis. However, it is unclear whether MCP-1 is able to modulate vascular smooth muscle cell (VSMC) proliferation. We assessed the effect of MCP-1 on VSMC proliferation and its interaction with serotonin (5-HT), a mitogen for VSMCs. Growth-arrested VSMCs were stimulated with different concentrations of MCP-1 (25-200 ng/ml) and 5-HT (5 and 50 microM) in serum-free medium. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. 5-HT at concentrations of 5 and 50 microM significantly stimulated DNA synthesis by 1.8- and 2.1-fold over the control value, respectively (p < 0.0001). However, MCP-1 at the concentrations tested did not have any significant effect on DNA synthesis. Even though MCP-1 (50 ng/ml) by itself is not mitogenic, when added to 5-HT, it significantly amplified the mitogenic effect of 5-HT compared with that of 5-HT alone (p < 0.0001). The 5-HT2A receptor antagonist sarpogrelate (10 microM) and its major metabolite M-1 (0.1 microM), pertussis toxin (10 ng/ml), Src family protein tyrosine kinase (PTK) inhibitor PP2 (1 microM), protein kinase C (PKC) inhibitor Ro31-8220 (0.1 microM) and mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 microM) significantly inhibited the mitogenic effect of 5-HT and its interaction with MCP-1. Anti-MCP-1 antibody (2 microg/ml) and the Janus kinase 2 (JAK2) inhibitor AG490 (10 microM) significantly inhibited the interaction of MCP-1 with 5-HT. Further, the amplified mitogenic effect of 5-HT with MCP-1 was completely reversed by the combined use of sarpogrelate with anti-MCP-1 antibody. Our results suggest that MCP-1 amplifies the mitogenic effect of 5-HT on VSMCs. The mitogenic effect of 5-HT may be mediated by the G protein-Src family PTK-PKC-MAPK pathway. The activation of the JAK2/signal transducer and activator of transcription 3 pathway by MCP-1 in addition to the MAPK pathway by 5-HT may explain the potentiating effect of MCP-1 on 5-HT-induced mitogenesis.
 ...
PMID:Monocyte chemotactic protein 1 amplifies serotonin-induced vascular smooth muscle cell proliferation. 1145 5

The hematopoietic-specific Galpha16 protein has recently been shown to mediate receptor-induced activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727. Galpha16QL-induced STAT3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (ERK1), but was inhibited by U0126, a Raf-1 inhibitor, and coexpression of the dominant negative mutants of Ras and Rac1. Inhibition of phospholipase Cbeta, protein kinase C, and calmodulin-dependent kinase II by their respective inhibitors also suppressed Galpha16QL-induced STAT3 activation. The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants. In contrast, c-Jun N-terminal kinase, p38 MAPK, RhoA, Cdc42, phosphatidylinositol 3-kinase, and the epidermal growth factor receptor did not appear to be required. Similar observations were obtained with human erythroleukemia cells, where STAT3 phosphorylation was stimulated by C5a in a PTX-insensitive manner. Collectively, these results highlight the important regulatory roles of the Ras/Raf/MEK/ERK and c-Src/JAK pathways on the stimulation of STAT3 by activated Galpha16. Demonstration of the involvement of different kinases in Galpha16QL-induced STAT3 activation supports the involvement of multiple signaling pathways in the regulation of transcription by G proteins.
 ...
PMID:Constitutively active Galpha16 stimulates STAT3 via a c-Src/JAK- and ERK-dependent mechanism. 1455 Dec 13

Our understanding of the phenomenon of myocardial vascular growth is very limited even though various studies have been conducted in several different models, because the focus in each has been on a select very few number of proteins as the possible growth factors. In the present study, we used the ischemic preconditioning (IP) model in the form of four in vivo repetitive cycles of coronary artery occlusion, each followed by reperfusion as the model to stimulate vascular growth, and performed the protein profiling using high-throughput antibody array technology. Rats were divided into two groups: control + left anterior descending coronary artery (LAD) occlusion (CMI), and IP+ LAD occlusion (IPMI). The antibody array experiment performed to compare the expression of 512 proteins between the IPMI and CMI samples revealed significant upregulation of growth proteins like TGF-beta, BMX, granulocyte-monocyte colony-stimulating factor, signal transducer and activator of transcription 3, alpha- and beta-catenins, ubiquitin-conjugating enzyme UbcH6, nexilin, and PKC-epsilon and -lambda. JNK1 and c-Src tyrosine kinase were expectedly found to be downregulated. Western blot experiments validated the changes in expression of these proteins. Therefore, this study puts forward the above-mentioned proteins as valid participants in the vascular growth signals that are known to be triggered by ischemic preconditioning of heart.
 ...
PMID:Potential candidates for ischemic preconditioning-associated vascular growth pathways revealed by antibody array. 1566 47

We performed microarray analyses on RNA from human intestinal epithelial (HT-29) cells treated with the cytotoxic enterotoxin (Act) of Aeromonas hydrophila to examine global cellular transcriptional responses. Based on three independent experiments, Act upregulated the expression of 34 genes involved in cell growth, adhesion, signaling, immune responses (including interleukin-8 [IL-8] production), and apoptosis. We verified the upregulation of 14 genes by real-time reverse transcriptase-PCR and confirmed Act-induced production of IL-8 by enzyme-linked immunosorbent assay on supernatants from nonpolarized and polarized HT-29 cells. Maximal production of IL-8 in response to Act required the presence of intracellular calcium, since chelation of calcium with BAPTA-AM significantly reduced Act-induced IL-8 production in HT-29 cells. We also examined activation of mitogen-activated protein kinases and, as demonstrated by Western blot analysis of apical side-treated polarized HT-29 cells, Act induced phosphorylation of p38, c-Jun NH(2)-terminal kinase, and extracellular signal-regulated kinase 1/2. In addition, KinetWorks proteomics screening of whole-cell lysates revealed Act-induced phosphorylation of cyclic AMP-response element binding protein (CREB), c-Jun, adducin, protein kinase C, and signal transducer and activator of transcription 3 (STAT3) and decreased phosphorylation of protein kinase Balpha, v-raf-1 murine leukemia viral oncogene homolog 1 (i.e., Raf1), and STAT1. We verified activation of CREB and activator protein 1 in polarized cells by gel shift assay. This is the first description of human intestinal epithelial cell transcriptional alterations, phosphorylation or activation of signaling molecules, cytokine production, and calcium mobilization in response to this toxin.
 ...
PMID:Microarray and proteomics analyses of human intestinal epithelial cells treated with the Aeromonas hydrophila cytotoxic enterotoxin. 1584 65

Failure of severed adult CNS axons to regenerate could be attributed to both a reduced intrinsic capacity to grow and an heightened susceptibility to inhibitory factors of the CNS extracellular environment. A particularly interesting and useful paradigm for investigating CNS axonal regeneration is its enhancement at the CNS branch of dorsal root ganglion (DRG) neurons after conditional lesioning of their peripheral branch. Recent reports have implicated the involvement of two well-known signaling pathways utilizing separate transcription factors; the Cyclic AMP (cAMP) response element binding protein (CREB) and signal transducer and activator of transcription 3 (STAT3), in conditional lesioning. The former appears to be the pathway activated by neurotrophic factors and Bcl-2, while the latter is responsible for the neurogenic effect of cytokines [such as the leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) elevated at lesion sites]. Recent findings also augmented earlier notions that modulations of the activity of another class of cellular signaling intermediate, the conventional protein kinase C (PKC), could result in a contrasting growth response by CNS neurons to myelin-associated inhibitors. We discuss these signaling pathways and mechanisms, in conjunction with other recent reports of regeneration enhancement and also within the context of what is known about aiding regeneration of injured CNS axons.
 ...
PMID:Axonal regeneration in adult CNS neurons--signaling molecules and pathways. 1647 81

We have previously shown that the immobilized extracellular matrices (ECMs) initiate cell migration and soluble growth factors (GFs) further enhance ECM-initiated cell migration. GFs alone cannot initiate cell migration. To further investigate the specificity of the two signaling mechanisms, we focused on the protein kinase C (PKC) family genes in primary human dermal fibroblasts (DFs). We here show that platelet-derived growth factor-BB (PDGF-BB) strongly stimulates membrane translocation and leading edge clustering of protein kinase Cdelta (PKCdelta). In contrast, attachment to collagen matrix alone does not cause the translocation. Although the kinase function of PKCdelta is dispensable for initial membrane translocation, it is critical for its sustained presence at the cells's leading edge. Blockade of endogenous PKCdelta signaling with dominant-negative kinase-defective PKC (PKCdelta-KD) or PKCdelta-small interfering RNA (siRNA) completely inhibited PDGF-BB-stimulated DF migration. In contrast, neither PKCdelta-KD nor PKCdelta-siRNA affected collagen-induced initiation of DF migration. Overexpression of a constitutively activated PKCdelta (PKCdelta-R144/145A) partially mimics the effect of PDGF-BB. However, PKCdelta-KD, PKCdelta-siRNA, or PKCdelta-R144/145A does not affect PDGF-BB-stimulated activation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase1/2, or c-Jun N-terminal kinase. Instead, inhibition of PKCdelta blocks PDGF-BB-stimulated activation of signal transducer and activator of transcription 3 (Stat3). This study unveiled the specificity of PKCdelta in the control of DF migration.
 ...
PMID:PKCdelta clustering at the leading edge and mediating growth factor-enhanced, but not ecm-initiated, dermal fibroblast migration. 1654 2


1 2 3 4 Next >>