Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotine is an important component in cigarette smoke that can activate the growth-promoting pathways to facilitate the development of lung cancer. However, the intracellular mechanism(s) by which nicotine promotes survival of lung cancer cells remains enigmatic. Bad is a proapoptotic BH3-only member of the Bcl2 family and is expressed in both small cell lung cancer and non-small cell lung cancer cells. Here we report that nicotine potently induces Bad phosphorylation at Ser112, Ser136, and Ser155 in a mechanism involving activation of MAPKs ERK1/2, PI3K/AKT, and PKA in human lung cancer cells. Nicotine-induced multi-site phosphorylation of Bad results in sequestering Bad from mitochondria and subsequently interacting with 14-3-3 in the cytosol. Treatment of cells with PKC inhibitor (staurosporine), MEK-specific inhibitor (PD98059), PI3 kinase inhibitor (LY294002), or PKA inhibitor (H89) blocks the nicotine-induced Bad phosphorylation that is associated with enhanced apoptotic cell death. The fact that beta-adrenergic receptor inhibitor (propranolol) blocks nicotine-induced activation of ERK1/2, AKT, PKA, Bad phosphorylation, and cell survival suggests that nicotine-induced Bad phosphorylation may occur through the upstream beta-adrenergic receptors. The fact that specific knockdown of Bad expression by RNA interference using short interfering RNA enhances cell survival and that nicotine has no additional survival effect on these cells suggests that Bad may act as a required target of nicotine. Thus, nicotine-induced survival may occur in a mechanism through multi-site phosphorylation of Bad, which may lead to development of human lung cancer and/or chemoresistance.
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PMID:Nicotine induces multi-site phosphorylation of Bad in association with suppression of apoptosis. 1503 18

Thyrotropin (TSH) is considered the main regulator of thyrocyte differentiation and proliferation. Thus, the characterization of the different signaling pathways triggered by TSH on these cells is of major interest in order to understand the mechanisms implicated in thyroid pathology. In this review we focus on the different signaling pathways involved in TSH-mediated proliferation and their role in thyroid transformation and tumorigenesis. TSH mitogenic activities are mediated largely by cAMP, which in turn may activate protein kinase (PKA)-dependent and independent processes. We analyze the effects of increased cAMP levels and PKA activity during cell cycle progression and the role of this signaling pathway in thyroid tumor initiation. Alternative pathways to PKA in the cAMP-mediated proliferation appear to involve the small GTPases Rap1 and Ras. We analyze the Ras effectors (PI3K, RalGDS and Raf) that are thought to mediate its oncogenic activity, as well as the ability of Ras to induce apoptosis in thyrocytes. Finally, we discuss the activation of the PLC/PKC cascade by TSH in thyroid cells and the role of this signaling pathway in the TSH-mediated proliferation and tumorigenesis.
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PMID:TSH-activated signaling pathways in thyroid tumorigenesis. 1506 72

Granulocytes are critical components of the innate immune system whose lifespan is limited by an intrinsic, constitutive, apoptotic pathway. However, the lifespan of these cells can be extended at an inflammatory locus through interaction with survival factors. Although a wide variety of factors can modulate granulocyte survival, they often utilize a common subset of intracellular signal transduction pathways. Over the last decade, evidence has accumulated that the PI3K (phosphatidylinositol 3-kinase) family of lipid kinases may be critical in regulating the ability of granulocytes to survive at inflammatory loci. Studies utilizing both pharmacological inhibitors of PI3K and isoform-specific knockout mice have demonstrated that this enzyme is needed for the anti-apoptotic effects of granulocyte survival factors. More recently, a serine/threonine protein kinase, termed protein kinase B (also known as c-akt), has been demonstrated to be important in modulating the prosurvival effects of PI3K activation. This can occur through modulation of the expression or phosphorylation of members of the Bcl-2 (B-cell lymphocytic-leukaemia proto-oncogene 2) family of apoptosis regulators. This review summarizes recent results that have implicated a role for PI3K in regulating granulocyte survival.
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PMID:Regulation of granulocyte apoptosis by phosphatidylinositol 3-kinase. 1515 66

A hybrid cell line, IOSE-Ov29, was created through fusion of cells from the human ovarian adenocarcinoma line OVCAR3 and the non-tumorigenic SV40 Tag-transfected human ovarian surface epithelial line IOSE-29. OVCAR3 cells exhibit a differentiated epithelial phenotype, whereas line IOSE-29 expresses mesenchymal characteristics that were acquired in culture by epithelio-mesenchymal transition. Microsatellite analysis, comparative genomic hybridization (CGH), and MFISH showed the genotype of the IOSE-Ov29 cells to contain components of both parent cell lines, but to be predominantly OVCAR3 derived. IOSE-Ov29 resembled OVCAR3 and differed from IOSE-29 as shown by its unlimited life span, tumorigenicity, epithelial morphology, keratin, occludin, E-cadherin and CA125 expression, increased expression of kinases of the PI3K pathway, and loss of cGMP-dependent protein kinase expression. IOSE-29-derived properties included SV40 Tag expression, growth inhibition by activin, collagen type III secretion, increased adhesion and spreading on tissue culture plastic, and increased growth rate. Proliferation of all three lines was stimulated by FSH and ATP and inhibited by GnRH I and GnRH II. Interestingly, IOSE-Ov29 was more anchorage independent than either parent line and was the only line that invaded Matrigel in Boyden chambers and formed invasive branches in collagen gels. The results indicate that IOSE-Ov29 is an IOSE-29/OVCAR3 hybrid, which differs from both parent lines genetically and phenotypically. Unexpectedly, fusion with the non-tumorigenic IOSE-29 cells enhanced malignancy-associated characteristics of OVCAR3, presumably as a result of the expression of IOSE-29-derived mesenchymal properties that are usually acquired by carcinoma cells through epithelio-mesenchymal transition during metastatic progression.
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PMID:Epithelio-mesenchymal transition in a neoplastic ovarian epithelial hybrid cell line. 1515 38

MUC4: encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-beta, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-beta in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4+/Smad4-), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4-/Smad4+), were used. By RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-beta, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-beta induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-beta activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to histone deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-beta is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-beta as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.
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PMID:A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-beta in pancreatic carcinogenesis. 1518 72

The mechanisms by which c-erbB-dependent signaling contribute to the invasive potential of HNSCC remain to be fully elucidated. We have previously shown that c-erbB autocrine and/or paracrine stimulation upregulates MMP-9 but has no effect on the related gelatinase, MMP-2. BTC, a major c-erbB ligand, has the ability to efficiently activate all c-erbB receptors and to bind directly to EGFR and c-erbB-4. BTC is commonly expressed in HNSCC cells and exerts the most potent effects in terms of MMP induction relative to other c-erbB ligands so far tested. In the present study, we explored the contribution of major downstream events triggered by BTC/c-erbB receptor signaling to the regulation of MMP-9 and in vitro invasiveness of HNSCC cells. In human HNSCC cell lines, SIHN-006 and Detroit-562, BTC treatment resulted in rapid tyrosine phosphorylation of all c-erbB receptors whereas both endogenous MMP-9 and BTC-stimulated MMP-9 were predominantly mediated via EGFR. BTC induced ERK1/2, JNK/SAPK and Akt phosphorylation with differing kinetics but not p38 kinase. The BTC-dependent activation of JNK and PI3K/Akt pathways occurred predominantly via EGFR, whereas activation of the MEK-1/ERK pathway occurred via all 4 c-erbB receptors, although again predominantly via EGFR. Selective inhibition of ERK/MAPK (by PD98059 or U0126) and PI3K (by LY294002 or wortmannin) led to marked reduction of both basal and BTC-induced MMP-9 activity and invasive ability of HNSCC cells. In contrast, inhibition of p38 kinase with SB203580 produced no such effects. A specific inhibitor of NF-kappa B, BAY 11-7085, also blocked the stimulatory effect of BTC. No remarkable inhibition of MMP-9 and invasion was observed on targeting other cellular activities, such as PKA, PKC and PLC-gamma. Taken together, our data show that BTC induces MMP-9 production and invasion primarily through activation of EGFR, MAPK and PI3K/Akt in HNSCC cells.
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PMID:Signaling pathways required for matrix metalloproteinase-9 induction by betacellulin in head-and-neck squamous carcinoma cells. 1519 68

The Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell cycle progression, cell adhesion, and motility. In this study, we report that stimulation of TLR2 in human epithelial and monocytic cells leads to rapid and transient activation of RhoA. RhoA cooperated with the canonical I-kappaB kinase-mediated pathway that induces the release of NF-kappaB, in regulating the trans activation of the NF-kappaB subunit p65/RelA by affecting Ser(311) phosphorylation, and subsequent cytokine production. Another consequence of TLR2 stimulation by bacterial derived products was the activation of atypical protein kinase C (PKC) zeta and association of this protein kinase with RhoA. Inhibition of PKCzeta decreased NF-kappaB activation and p65/RelA trans activation without affecting I-kappaBalpha degradation. The observation of a transient, stimulus-dependent association of RhoA with PKCzeta suggests that RhoA mediates at least partially its effect on gene transcription through atypical PKC. In contrast to previous studies, identifying Rac1-PI3K as an upstream element in TLR2-initiated response to NF-kappaB, PI3K signaling was not required for RhoA or PKCzeta activity. These results indicate that multiple GTPase-regulated pathways emerge from stimulated Toll receptors, controlling different aspects of NF-kappaB-mediated gene transcription.
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PMID:The low molecular weight GTPase RhoA and atypical protein kinase Czeta are required for TLR2-mediated gene transcription. 1521 Aug 11

We report on the case of a patient with a diagnosis of a HER2-overexpressing metastatic breast cancer which was refractory to a combination of a Raf kinase inhibitor and docetaxel, but highly sensitive to trastuzumab, a HER2-targeted monoclonal antibody. Interestingly, there was no evidence of Ras-Raf-MAPK or PI3K-Akt pathways activation.
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PMID:Exquisite antitumour response to trastuzumab in a patient with no evidence of Ras-Raf-MAPK and PI3K-Akt pathways activation. 1576 91

Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C-theta (PKC-theta), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-theta are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-theta KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40-50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated PI3K activity. In contrast, PKC-theta inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-theta is a potential therapeutic target for the treatment of type 2 diabetes.
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PMID:PKC-theta knockout mice are protected from fat-induced insulin resistance. 1537 6

Although the PI3K (phosphatidylinositol 3-kinase) pathway typically regulates cell growth and survival, increasing evidence indicates the involvement of this pathway in neural plasticity. It is unknown whether the PI3K pathway can mediate pain hypersensitivity. Intradermal injection of capsaicin and NGF produce heat hyperalgesia by activating their respective TRPV1 (transient receptor potential vanilloid receptor-1) and TrkA receptors on nociceptor sensory nerve terminals. We examined the activation of PI3K in primary sensory DRG neurons by these inflammatory agents and the contribution of PI3K activation to inflammatory pain. We further investigated the correlation between the PI3K and the ERK (extracellular signal-regulated protein kinase) pathway. Capsaicin and NGF induce phosphorylation of the PI3K downstream target AKT (protein kinase B), which is blocked by the PI3K inhibitors LY294002 and wortmannin, indicative of the activation of PI3K by both agents. ERK activation by capsaicin and NGF was also blocked by PI3K inhibitors. Similarly, intradermal capsaicin in rats activated PI3K and ERK in C-fiber DRG neurons and epidermal nerve fibers. Injection of PI3K or MEK (ERK kinase) inhibitors into the hindpaw attenuated capsaicin- and NGF-evoked heat hyperalgesia but did not change basal heat sensitivity. Furthermore, PI3K, but not ERK, inhibition blocked early induction of hyperalgesia. In acutely dissociated DRG neurons, the capsaicin-induced TRPV1 current was strikingly potentiated by NGF, and this potentiation was completely blocked by PI3K inhibitors and primarily suppressed by MEK inhibitors. Therefore, PI3K induces heat hyperalgesia, possibly by regulating TRPV1 activity, in an ERK-dependent manner. The PI3K pathway also appears to play a role that is distinct from ERK by regulating the early onset of inflammatory pain.
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PMID:Phosphatidylinositol 3-kinase activates ERK in primary sensory neurons and mediates inflammatory heat hyperalgesia through TRPV1 sensitization. 1538 13


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