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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adapter protein Shc was initially identified as an SH2 containing proto-oncogene involved in growth factor signaling. Since then a number of studies in multiple systems have implicated a role for Shc in signaling via many different types of receptors, such as growth factor receptors, antigen receptors, cytokine receptors, G-protein coupled receptors, hormone receptors and integrins. In addition to the ubiquitous ShcA, two other shc gene products, ShcB and ShcC, which are predominantly expressed in neuronal cells, have also been identified. ShcA knockout mice are embryonic lethal and have clearly suggested an important role for ShcA in vivo. Based on dominant negative studies and mouse embryos deficient in ShcA, a clear role for Shc in leading to mitogen activated protein kinase (MAPK) activation has been established. However MAPK activation may not be the sole function of Shc proteins. Although Shc has also been linked to other signaling events such as c-Myc activation and cell survival, the mechanistic understanding of these signaling events remains poorly characterized. Given the apparently central role that Shc plays signaling via many receptors, delineating the precise mechanism(s) of Shc-mediated signaling may be critical to our understanding of the effects mediated through these receptors.
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PMID:Signaling via Shc family adapter proteins. 1160 35

Silibinin, quercetin, and epigallocatechin 3-gallate (EGCG) have been shown to be skin cancer-preventive agents, albeit by several different mechanisms. Here, we assessed whether these agents show their cancer-preventive potential by a differential effect on mitogenic signaling molecules and cell cycle regulators. Treatment of human epidermoid carcinoma A431 cells with these agents inhibited the activation of the epidermal growth factor receptor and the downstream adapter protein Shc, but only silibinin showed a marked inhibition of mitogen-activated protein kinase-extracellular signal-regulated kinase-1 and -2 activation. In terms of cell cycle regulators, silibinin treatment showed an induction of Cip1/p21 and Kip1/p27 together with a significant decrease in cyclin-dependent kinase (CDK)-4, CDK2, and cyclin D1. Quercetin treatment, however, resulted in a moderate increase in Cip1/p21 with no change in Kip1/p27 and a decrease in CDK4 and cyclin D1. EGCG treatment also led to an induction of Cip1/p21 but no change in Kip1/27, CDK2, and cyclin D1 and a decrease in CDK4 only at low doses. Treatment of cells with these agents resulted in a strong dose- and time-dependent cell growth inhibition. A high dose of silibinin and low and high doses of quercetin and EGCG also led to cell death by apoptosis, suggesting that a lack of their inhibitory effect on mitogen-activated protein kinase-extracellular signal-regulated kinase-1 and -2 activation possibly "turns on" an apoptotic cell death response associated with their cancer-preventive and anticarcinogenic effects. Together, these results suggest that silibinin, quercetin, and EGCG exert their cancer-preventive effects by differential responses on mitogenic signaling and cell cycle regulators.
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PMID:Differential responses of skin cancer-chemopreventive agents silibinin, quercetin, and epigallocatechin 3-gallate on mitogenic signaling and cell cycle regulators in human epidermoid carcinoma A431 cells. 1175 94

Toll-like receptor 2 (TLR2) agonists induce a subset of TLR4-inducible proinflammatory genes, which suggests the use of differential signaling pathways. Murine macrophages stimulated with the TLR4 agonist Escherichia coli lipopolysaccharide (LPS), but not with TLR2 agonists, induced phosphorylation of signal transducer and activator of transcription 1alpha (STAT1alpha) and STAT1beta, which was blocked by antibodies to interferon beta (IFN-beta) but not IFN-alpha. All TLR2 agonists poorly induced IFN-beta, which is encoded by an immediate early LPS-inducible gene. Thus, the failure of TLR2 agonists to induce STAT1-dependent genes resulted, in part, from their inability to express IFN-beta. TLR4-induced IFN-beta mRNA was MyD88- and PKR (double-stranded RNA-dependent protein kinase)-independent, but TIRAP (Toll-interleukin 1 receptor domain-containing adapter protein)-dependent. Together, these findings provide the first mechanistic basis for differential patterns of gene expression activated by TLR4 and TLR2 agonists.
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PMID:TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. 1189 92

Although Gbetagamma is thought to mediate mitogen-activated protein kinase (MAPK) activation in response to G protein-coupled receptor stimulation, the mechanisms involved in this pathway have not been clearly defined. Phosphoinositide 3-kinase (PI3K) has been proposed as an early intermediate in this process, but its role has remained elusive. We have observed that dominant negative mutants of p110beta, but not of p110gamma, inhibited MAPK stimulation in response to lysophosphatidic acid (LPA). The role of p110beta was located upstream from Ras. To determine which of the lipid or protein kinase activities of p110beta were important for Ras activation, we produced a mutant p110beta lacking the lipid but not the protein kinase activity. This protein displayed a dominant negative activity similar to a kinase-dead mutant, indicating that p110beta lipid kinase activity was essentially involved in Ras activation. In agreement, overexpression of the lipid phosphatase PTEN was found to specifically inhibit Ras stimulation induced by LPA. In addition, we have observed that the PH domain-containing adapter protein Gab1, which is involved in p110beta activation during LPA stimulation, is also implicated in this pathway downstream of p110beta. Indeed, both membrane redistribution and phosphorylation of Gab1 were reduced in the presence of PI3K inhibitors or dominant negative p110beta. Downstream of Gab1, the tyrosine phosphatase SHP2 was found to mediate Ras activation in response to LPA and to be recruited through PI3K and Gab1, because transfection of Gab1 mutant deficient for SHP2 binding inhibited Ras activation without interfering with PI3K activation. We conclude that LPA-induced Ras activation is mediated by a p110beta/Gab1/SHP2 pathway. Moreover, we present data indicating that p110beta is effectively the target of betagamma in this pathway, suggesting that the p110beta/Gab1/SHP2 pathway provides a novel link between betagamma and Ras by integrating two early events of LPA signaling, i.e. Gbetagamma release and tyrosine kinase receptor transactivation.
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PMID:A function for phosphoinositide 3-kinase beta lipid products in coupling beta gamma to Ras activation in response to lysophosphatidic acid. 1191 60

The initial signaling events underlying the chemotactic response of Escherichia coli to aspartic acid occur within a ternary complex that includes Tar (an aspartate receptor), CheA (a protein kinase), and CheW. Because CheW can bind to CheA and to Tar, it is thought to serve as an adapter protein in this complex. The functional importance of CheW binding interactions, however, has not been investigated. To better define the role of CheW and its binding interactions, we performed biochemical characterization of six mutant variants of CheW. We examined the ability of the purified mutant CheW proteins to bind to CheA and Tar, to promote formation of active ternary complexes, and to support chemotaxis in vivo. Our results indicate that mutations which eliminate CheW binding to Tar (V36M) or to CheA (G57D) result in a complete inability to form active ternary complexes in vitro and render the CheW protein incapable of mediating chemotaxis in vivo. The in vivo signaling pathway can, however, tolerate moderate changes in CheW-Tar and CheW-CheA affinities observed with several of the mutants (G133E, G41D, and 154ocr). One mutant (R62H) provided surprising results that may indicate a role for CheW in addition to binding CheA/receptors and promoting ternary complex formation.
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PMID:CheW binding interactions with CheA and Tar. Importance for chemotaxis signaling in Escherichia coli. 1192 83

PAK1 is a protein kinase downstream of the small GTPases Rac and Cdc42 that previous work has implicated in endothelial cell migration via modulation of cell contraction. The first proline-rich region of PAK that binds to an SH3 domain from the adapter protein NCK was responsible for these dominant-negative effects. To test the role of PAK in angiogenesis, we prepared a peptide in which the proline-rich region was fused to the polybasic sequence from the HIV Tat protein to facilitate entry into cells. We show that the short peptide selectively binds NCK, whereas a mutant peptide does not. Treatment of cells with the PAK peptide but not the control peptide disrupts localization of PAK. This peptide specifically inhibited endothelial cell migration and contractility similarly to full-length dominant-negative PAK. In an in vitro tube-forming assay, the PAK peptide specifically blocked formation of multicellular networks. In an in vivo chick chorioallantoic membrane assay, the PAK peptide specifically blocked angiogenesis. These results, therefore, suggest a role for PAK in angiogenesis.
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PMID:A dominant-negative p65 PAK peptide inhibits angiogenesis. 1193 38

Bradykinin (BK) has been implicated in the regulation of renal function. Activation of extracellular signal-regulated protein kinase (ERK1/2) has been demonstrated in several models of toxic or proliferative renal injury. We studied activation of ERK1/2 by BK in a cell model of the most distal part of the nephron, inner medullary collecting duct (mIMCD-3) cells. Exposure of mIMCD-3 cells to BK (10(-10)-10(-5) M) resulted in a concentration-dependent increase in tyrosine phosphorylation of ERK1/2, with maximal effect at 10(-8) M BK. ERK1/2 activation by BK was observed as early as 1 min, peaked at 5 min, and was sustained at least for 1 h. The effect of BK was mediated by the B(2) receptor and was pertussis toxin-independent. Inhibition of phospholipase C, protein kinase C, or phosphatidylinositol 3-kinase did not alter ERK1/2 activation by BK. BK-induced ERK1/2 activation was Ca(2+)-calmodulin-independent but was sensitive to genistein, an inhibitor of tyrosine kinase(s). AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) kinase, completely blocked the effect of BK, suggesting an essential role of EGFR in ERK1/2 activation by BK. Immunoprecipitation/Western blot studies revealed that BK stimulated tyrosine phosphorylation of EGFR, its association with an adapter molecule Grb2, and complex formation between Grb2 and the adapter protein Shc. Activation studies of monomeric G protein Ras showed that BK-induced stimulation of Ras was dependent on EGFR tyrosine kinase activity. These studies demonstrate that BK stimulates Ras-dependent activation of ERK1/2 in mIMCD-3 cells via transactivation of EGFR through a novel mechanism.
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PMID:Bradykinin B2 receptor activates extracellular signal-regulated protein kinase in mIMCD-3 cells via epidermal growth factor receptor transactivation. 1260 71

p90 ribosomal S6 kinase 1 (RSK1) is a serine/threonine kinase that is activated by extracellular signal-related kinases 1/2 and phosphoinositide-dependent protein kinase 1 upon mitogen stimulation. Under basal conditions, RSK1 is located in the cytosol and upon stimulation, RSK1 translocates to the plasma membrane where it is fully activated. The ability of RSK1 to bind the adapter protein 14-3-3beta was investigated because RSK1 contains several putative 14-3-3-binding motifs. We demonstrate that RSK1 specifically and directly binds 14-3-3beta. This interaction was dependent on phosphorylation of serine 154 within the motif RLSKEV of RSK1. Binding of RSK1 to 14-3-3beta was maximal under basal conditions and decreased significantly upon mitogen stimulation. After 5 min of serum stimulation, a portion of 14-3-3beta and RSK1 translocated to the membrane fraction, and immunofluorescence studies demonstrated colocalization of RSK1 and 14-3-3beta at the plasma membrane in vivo. Incubation of recombinant RSK1 with 14-3-3beta decreased RSK1 kinase activity by approximately 50%. Mutation of RSK1 serine 154 increased both basal and serum-stimulated RSK activity. In addition, the epidermal growth factor response of RSK1S154A was enhanced compared with wild type RSK. The amount of RSK1S154A was significantly increased in the membrane fraction under basal conditions. Increased phosphorylation of two sites essential for RSK1 kinase activity (Ser(380) and Ser(363)) in RSK1S154A compared with RSK1 wild type, demonstrated that 14-3-3 interferes with RSK1 phosphorylation. These data suggest that 14-3-3beta binding negatively regulates RSK1 activity to maintain signal specificity and that association/dissociation of the 14-3-3beta-RSK1 complex is likely to be important for mitogen-mediated RSK1 activation.
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PMID:14-3-3beta is a p90 ribosomal S6 kinase (RSK) isoform 1-binding protein that negatively regulates RSK kinase activity. 1261 28

Cellular proliferation is controlled by the integration and coordination of extracellular signals. This study explores the role of the protein annexin 1 (ANXA1) in the regulation of such events. We show that ANXA1 has a cell-type independent, anti-proliferative function through sustained activation of the ERK signaling cascade. Moreover, ANXA1 reduces proliferation by ERK-mediated disruption of the actin cytoskeleton and ablation of cyclin D1 protein expression and not by ERK-mediated induction of the cyclin-dependent kinase, CDK2, inhibitor p21(cip/waf). Finally, ANXA1 regulates the ERK pathway at a proximal location, by SH2 domain-independent association with the adapter protein Grb-2. In summary, overexpression of ANXA1 mediates the disruption of normal cell morphology and inhibits cyclin D1 expression, therefore reducing cell proliferation through proximal modulation of the ERK signal transduction pathway.
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PMID:Annexin 1 regulates cell proliferation by disruption of cell morphology and inhibition of cyclin D1 expression through sustained activation of the ERK1/2 MAPK signal. 1451 91

To gain insight into the mechanism by which the adapter protein SH2-B promotes nerve growth factor (NGF)-mediated neuronal differentiation and survival, the effect of SH2-B on the serine/threonine kinase Akt/protein kinase B and downstream effector proteins was examined. PC12 cells stably overexpressing SH2-Bbeta, which exhibit enhanced NGF-induced neuronal differentiation compared with control cells, showed enhanced and prolonged NGF-induced phosphorylation of Akt on Ser473 and Akt enzymatic activity. Surprisingly, NGF-induced phosphorylation of Akt on Ser473 and Akt activity were not altered in cells overexpressing SH2-Bbeta(R555E) with a defective SH2 domain, despite the ability of the overexpressed SH2-Bbeta(R555E) to block NGF-induced differentiation. Consistent with SH2-Bbeta enhancing the activity of Akt, cells overexpressing SH2-Bbeta but not SH2-Bbeta(R555E) exhibited increased and/or prolonged phosphorylation of the pro-apoptotic Akt effector proteins, glycogen synthase kinase-3, and forkhead transcription factors, FKHRL1/FOXO3 and FKHR/FOXO1. Immunolocalization studies indicated that, although ectopically expressed FKHR was primarily concentrated in the cytoplasm of control cells and cells transiently overexpressing SH2-Bbeta, it was concentrated in the nucleus of cells transiently overexpressing SH2-Bbeta(R555E). Similarly, SH2-Bbeta stimulated the accumulation of FKHR in the cytoplasm of 293T and COS-7 cells, whereas SH2-Bbeta(R555E) enhanced its accumulation in the nucleus. In PC12 cells stably expressing forms of SH2-Bbeta, SH2-Bbeta mimicked the ability of NGF to promote redistribution of FKHR to the cytoplasm whereas SH2-Bbeta(R555E) blocked this effect of NGF. Taken together, these data indicate that SH2-B is a positive regulator of NGF-mediated activation of the Akt/Forkhead pathway.
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PMID:SH2-B is a positive regulator of nerve growth factor-mediated activation of the Akt/Forkhead pathway in PC12 cells. 1456 60


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