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)

Integrin adhesion receptors are critical for antigen recognition by T cells and for regulated recirculation and trafficking into and through various tissues in the body. T-cell receptor (TCR) signaling induces rapid increases in integrin function that facilitate T-cell activation by promoting stable contact with antigen-presenting cells and extracellular proteins in the environment. In this review, we outline the molecular mechanisms by which the TCR signals to integrins and present a model that highlights four key events: (i) initiation of proximal TCR signals nucleated by the linker for activated T cells (LAT) adapter protein and involving Itk, phospholipase C-gamma1, Vav1, and Src homology 2 domain-containing leukocyte-specific phosphoprotein of 76 kDa; (ii) transmission of integrin activation signals from the LAT signalosome to integrins by protein kinase (PK) C and the adapter protein, adhesion and degranulation-promoting adapter protein; (iii) assembly of integrin-associated signaling complexes that include PKD, the guanosine triphosphatase Rap1 and its effectors, and talin; and (iv) reorganization of the actin cytoskeleton by WAVE2 and other actin-remodeling proteins. These events coordinate changes in integrin conformation and clustering that result in enhanced integrin functional activity following TCR stimulation.
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PMID:T-cell receptor signaling to integrins. 1762 44

Src kinase-associated phosphoprotein of 55 kDa (SKAP55) is an adapter protein with an N-terminal region, a pleckstrin homology domain, a linker with tyrosine phosphorylation sites, and a C-terminal Src homology 3 domain. We report that overexpression of SKAP55 disrupts signaling from the TCR to the Ras-Erk-AP-1 pathway and transcription of the IL-2 gene in primary human T cells and in Jurkat T leukemia cells. In contrast, moderate overexpression of SKAP55 increased TCR-dependent AP-1 transcriptional activity, suggesting that high-level SKAP55 overexpression interfered with the assembly of functional signaling complexes required for TCR coupling to the Ras pathway. In support of this view, knock-down of SKAP55 by RNA interference resulted in decreased reporter gene activation and decreased ERK phosphorylation. In contrast, TCR-induced NF-kappaB activation was not affected. Since constitutively active forms of Ras or Raf-1 overcame the inhibitory effects of SKAP55 overexpression, we searched for a mechanism upstream of Ras and found that SKAP55 co-immunoprecipitated with the Ras activator RasGRP1. The binding of RasGRP1 to SKAP55 required the C-terminus of SKAP55 and was enhanced by tyrosine phosphorylation of SKAP55. These results suggest that SKAP55 modulates signal transduction from the TCR to Ras by binding to RasGRP1.
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PMID:SKAP55 modulates T cell antigen receptor-induced activation of the Ras-Erk-AP1 pathway by binding RasGRP1. 1765 5

Left ventricular (LV) remodeling is known to contribute to morbidity and mortality after myocardial infarction (MI). Because LV remodeling is strongly associated with an inflammatory response, we investigated whether or not TLR-4 influences LV remodeling and survival in a mice model of MI. Six days after MI induction, TLR4 knockout (KO)-MI mice showed improved LV function 32 and reduced LV remodeling as indexed by reduced levels of atrial natriuretic factor and total collagen as well as by a reduced heart weight to body weight ratio when compared with WT-MI mice. This was associated with a reduction of protein levels of the intracellular TLR4 adapter protein MyD88 and enhanced protein expression of the anti-hypertrophic JNK in KO-MI mice when compared with wild-type (WT)-MI mice. In contrast, protein activation of the pro-hypertrophic kinases protein kinase Cdelta and p42/44 were not regulated in KO-MI mice when compared with WT-MI mice. Improved LV function, reduced cardiac remodeling, and suppressed intracellular TLR4 signaling in KO-MI mice were associated with significantly improved survival compared with WT-MI mice (62 vs 23%; p < 0.0001). TLR4 deficiency led to improved survival after MI mediated by attenuated left ventricular remodeling.
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PMID:Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice. 1845 17

Adiponectin is an adipocyte-derived cytokine that has attracted much attention because of its insulin-sensitizing effects in liver and skeletal muscle. Two adiponectin receptors, AdipoR1/R2, have been cloned, but relatively little is known about their intracellular signaling mechanisms. We found that full-length adiponectin rapidly and robustly activates the ERK1/2 mitogen-activated protein kinase pathway in primary vascular smooth muscle, vascular endothelial cells, and hepatocytes. In a HEK293 cell model, we found that downregulating AdipoR1/R2 simultaneously, but not individually, by RNA interference attenuated adiponectin-induced ERK1/2 activation, suggesting that either receptor was sufficient to mediate the response. Downregulation of T-cadherin, another adiponectin binding protein, enhanced the response. Downregulation of APPL1, an adapter protein and putative mediator of AdipoR1/R2 signaling, impaired adiponectin-stimulated ERK1/2 activation. Inhibiting PKA modestly attenuated ERK1/2 activation, while inhibition of Src family tyrosine kinases with PP2 abolished the response. The small GTPase inhibitor Clostridium difficile toxin B also produced complete inhibition. Adiponectin caused rapid, PP2-sensitive activation of Ras, but not the cAMP-regulated small GTPase, Rap1, suggesting that Src-dependent Ras activation is the dominant mechanism of adiponectin-stimulated ERK1/2 activation. To test whether Ras-ERK1/2 signaling by adiponectin was physiologically relevant, we determined the effects of overexpressing AdipoR1, adiponectin, or both on the rate of HEK293 cell growth. Overexpression of adiponectin alone, but not AdipoR1 alone, supported growth under serum-free conditions, while simultaneous expression of both led to further enhancement. These results suggest that adiponectin can exert proliferative effects by activating Ras signaling pathways.
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PMID:The adiponectin receptors AdipoR1 and AdipoR2 activate ERK1/2 through a Src/Ras-dependent pathway and stimulate cell growth. 1884 4

p66Shc is an adapter protein that is induced by hypertrophic stimuli and has been implicated as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. This study implicates p66Shc in an alpha(1)-adrenergtic receptor (alpha(1)-AR) pathway that requires the cooperative effects of protein kinase (PK)Cepsilon and PKCdelta and leads to AKT-FOXO3a phosphorylation in cardiomyocytes. alpha(1)-ARs promote p66Shc-YY(239/240) phosphorylation via a ROS-dependent mechanism that is localized to caveolae and requires epidermal growth factor receptor (EGFR) and PKCepsilon activity. alpha(1)-ARs also increase p66Shc-S(36) phosphorylation via an EGFR transactivation pathway involving PKCdelta. p66Shc links alpha(1)-ARs to an AKT signaling pathway that selectively phosphorylates/inactivates FOXO transcription factors and downregulates the ROS-scavenging protein manganese superoxide dismutase (MnSOD); the alpha(1)-AR-p66Shc-dependent pathway involving AKT does not regulate GSK3. Additional studies show that RNA interference-mediated downregulation of endogenous p66Shc leads to the derepression of FOXO3a-regulated genes such as MnSOD, p27Kip1, and BIM-1. p66Shc downregulation also increases proliferating cell nuclear antigen expression and induces cardiomyocyte hypertrophy, suggesting that p66Shc exerts an antihypertrophic action in neonatal cardiomyocytes. The novel alpha(1)-AR- and ROS-dependent pathway involving p66Shc identified in this study is likely to contribute to cardiomyocyte remodeling and the evolution of heart failure.
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PMID:p66Shc links alpha1-adrenergic receptors to a reactive oxygen species-dependent AKT-FOXO3A phosphorylation pathway in cardiomyocytes. 1916 39

Adhesive interactions between multiple myeloma (MM) cells and marrow stromal cells activate multiple signaling pathways including nuclear factor kappaB (NF-kappaB), p38 mitogen-activated protein kinase (MAPK), and Jun N-terminal kinase (JNK) in stromal cells, which promote tumor growth and bone destruction. Sequestosome-1 (p62), an adapter protein that has no intrinsic enzymatic activity, serves as a platform to facilitate formation of signaling complexes for these pathways. Therefore, we determined if targeting only p62 would inhibit multiple signaling pathways activated in the MM microenvironment and thereby decrease MM cell growth and osteoclast formation. Signaling through NF-kappaB and p38 MAPK was increased in primary stromal cells from MM patients. Increased interleukin-6 (IL-6) production by MM stromal cells was p38 MAPK-dependent while increased vascular cell adhesion molecule-1 (VCAM-1) expression was NF-kappaB-dependent. Knocking-down p62 in patient-derived stromal cells significantly decreased protein kinase Czeta (PKCzeta), VCAM-1, and IL-6 levels as well as decreased stromal cell support of MM cell growth. Similarly, marrow stromal cells from p62(-/-) mice produced much lower levels of IL-6, tumor necrosis factor-alpha (TNF-alpha), and receptor activator of NF-kappaB ligand (RANKL) and supported MM cell growth and osteoclast formation to a much lower extent than normal cells. Thus, p62 is an attractive therapeutic target for MM.
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PMID:Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation. 1928 58

Factors contained in physiological microenvironments in tissues where mast cells differentiate and reside may influence mast cell responsiveness and modify antigen-dependent activation. A possible direct or indirect role of mast cell responses in diabetes mellitus prompted us to study the impact of insulin treatment on antigen triggered signaling pathways downstream of FcepsilonRI in bone marrow-derived mouse mast cells (BMMCs). We found that insulin alone stimulates tyrosine phosphorylation of tyrosine kinases Lyn, Syk, Fyn, the adapter protein Gab2 (Grb2-associated binding protein 2), Akt and activates ERK, JNK and p38 kinase. Effect of insulin on FcepsilonRI signaling pathways was marked by enhanced phosphorylation of Lyn, Fyn, Gab2 and Akt. Furthermore, BMMC stimulated with antigen in the presence of insulin responded with enhanced protein kinase theta (PKCtheta) activity and increased JNK phosphorylation when compared to BMMC triggered with antigen alone. Functional studies reveal enhanced degranulation and altered cytoskeletal rearrangement when BMMCs were treated simultaneously with insulin and antigen. Our results suggest that insulin tunes antigen-mediated responses of mast cells.
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PMID:Insulin potentiates FcepsilonRI-mediated signaling in mouse bone marrow-derived mast cells. 2000 75

The protein kinase LKB1 is a crucial regulator of cell growth/proliferation and cell polarity and is the causative gene in the cancer-predisposing disease Peutz-Jeghers syndrome (PJS). The activity of LKB1 is greatly enhanced following its association with the Ste20-like adapter protein STRAD. Unlike LKB1 however, mutations in STRAD have not been identified in PJS patients and thus, the key tumour suppressive role(s) of LKB1 might be STRAD independent. Here, we report that Caenorhabditis elegans strd-1/STRAD mutants recapitulate many phenotypes typical of par-4/LKB1 loss of function, showing defects during early embryonic and dauer development. Interestingly, although the growth/proliferation defects in severe par-4 and strd-1 mutant dauers are comparable, strd-1 mutant embryos do not share the polarity defects of par-4 embryos. We demonstrate that most of par-4-dependent regulation of germline stem cell (GSC) quiescence occurs through AMPK, whereby PAR-4 requires STRD-1 to phosphorylate and activate AMPK. Consistent with this, even though AMPK plays a major role in the regulation of cell proliferation, like strd-1 it does not affect embryonic polarity. Instead, we found that the PAR-4-mediated phosphorylation of polarity regulators such as PAR-1 and MEX-5 in the early embryo occurs in the absence of STRD-1. Thus, PAR-4 requires STRD-1 to phosphorylate AMPK to regulate cell growth/proliferation under reduced insulin signalling conditions, whereas PAR-4 can promote phosphorylation of key proteins, including PAR-1 and MEX-5, to specify early embryonic polarity independently of STRD-1. Our results therefore identify a key strd-1/STRAD-independent function of par-4/LKB1 in polarity establishment that is likely to be important for tumour suppression in humans.
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PMID:Differential requirements for STRAD in LKB1-dependent functions in C. elegans. 2011 Mar 31

Aberrant adhesion signaling pathways in cancer cells underlie their deadly invasive capabilities. The adhesion-related PDZ adapter protein mda-9/syntenin is a positive regulator of cancer cell progression in breast cancer, melanoma, and other human cancers. In this study, we report that mda-9/syntenin mediates adhesion-mediated activation of protein kinase Calpha (PKCalpha) and focal adhesion kinase (FAK) by fibronectin (FN) in human breast cancer and melanoma cells. FN rapidly stimulated the expression of mda-9/syntenin and the activation of PKCalpha prior to activation of FAK. Inhibiting PKCalpha suppressed basal or FN-induced expression of mda-9/syntenin, as well as cell migration and invasion toward FN stimulated by mda-9/syntenin. Several lines of evidence suggested that activation of PKCalpha and expression of mda-9/syntenin were interdependent. First, mda-9/syntenin inhibition suppressed basal or FN-induced phosphorylation of PKCalpha at Thr(638/641), whereas PKCalpha inhibition suppressed basal or FN-induced expression of mda-9/syntenin. Second, inhibiting either mda-9/syntenin or PKCalpha suppressed FN-induced formation of integrin-beta(1)/FAK/c-Src signaling complexes. Third, inhibiting either mda-9/syntenin or PKCalpha suppressed FN-induced phosphorylation of FAK Tyr(397) and c-Src Tyr(416) and the induction of downstream effector signals to p38 and mitogen-activated protein kinase, Cdc42, and NF-kappaB. In summary, our findings offer evidence that mda-9/syntenin acts as a molecular adaptor linking PKCalpha and FAK activation in a pathway of FN adhesion by human breast cancer and melanoma cells.
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PMID:Activation of the integrin effector kinase focal adhesion kinase in cancer cells is regulated by crosstalk between protein kinase Calpha and the PDZ adapter protein mda-9/Syntenin. 2014 26

The adapter protein TRIF mediates signal transduction through TLR3 and TLR4, inducing production of type I IFNs and inflammatory cytokines. The present study investigates the mechanisms by which TRIF signaling controls TNF-alpha biosynthesis. We provide evidence that, in LPS-stimulated murine dendritic cells, TRIF stimulates TNF-alpha biosynthesis selectively at the posttranscriptional level by promoting mRNA translation. In the absence of functional TRIF, the production of TNF-alpha protein was severely impaired, whereas TNF-alpha mRNA levels and stability, as well as transcriptional activity of the Tnfa gene, were not affected. Similarly, TRIF was required for production of LPS-induced TNF-alpha protein, but not of mRNA, in bone marrow-derived macrophages. In peritoneal macrophages, however, TRIF was also required for normal induction of TNF-alpha mRNA, suggesting cell type-related functions of TRIF. The influence of TRIF on dendritic cell TNF-alpha production was independent of type I IFNs. TRIF was required for prolonged activation of MAPKs in LPS-stimulated dendritic cells but was dispensable for the activation of NF-kappaB. Inhibition of late p38 activity attenuated LPS-stimulated elevation of TNF-alpha protein but not mRNA levels. The p38 effector kinase MK2 was directly activated through the TRIF pathway of TLR4. Importantly, stimulation of Mk2(-/-) cells through TLR3 or TLR4 severely impaired TNF-alpha protein production but did not affect TNF-alpha mRNA induction. Together, these results indicate that the TRIF signaling pathway promotes TNF-alpha mRNA translation through activation of the protein kinase MK2.
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PMID:TRIF signaling stimulates translation of TNF-alpha mRNA via prolonged activation of MK2. 2037 3


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