Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Agglucetin, a platelet glycoprotein (GP)Ib binding protein from Formosan Agkistrodon acutus (A. acutus) venom, could sustain human umbilical vein endothelial cell (HUVEC) proliferation and HUVEC adhering to immobilized agglucetin showed extensive spreading, which was strongly abrogated by integrin antagonists 7E3 and triflavin. Flow cytometric analyses confirmed the expression of GPIb complex on HUVEC is absent and fluorescein isothiocyanate (FITC)-agglucetin binds to HUVEC in a dose-dependent and saturable manner. Furthermore, native agglucetin specifically and dose-dependently inhibited the binding of FITC-23C6, an anti-alphavbeta3 monoclonal antibody (mAb), but not antibodies against alpha2 and alpha5, toward HUVEC and purified alphavbeta3 also bound to immobilized agglucetin-beta in a dose-dependent manner. Moreover, agglucetin exhibited a pro-angiogenic effect in vitro, as well as the focal adhesion kinase (FAK)-associated signaling molecules responsible for HUVEC activation were initiated by agglucetin. In conclusion, agglucetin, acting as a survival factor, promotes endothelial adhesion and angiogenesis by triggering alphavbeta3 signaling through FAK/phosphatidylinositol 3-kinase (PI3K)/Akt pathway.
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PMID:Agglucetin, a tetrameric C-type lectin-like venom protein, regulates endothelial cell survival and promotes angiogenesis by activating integrin alphavbeta3 signaling. 1831 55

Clinical resistance to imatinib often occurs in the absence of a mutation in the BCR-ABL kinase domain. Imatinib is transported out of cells by the efflux transporter ABCB1 (MDR1, whose product is p-glycoprotein). By contrast, the influx transporter, human organic cation transporter 1 (hOCT1) (also known as SLC22A1), transports imatinib into cells. Recent studies have identified that patients with low expression or activity of hOCT1 have a lower probability of achieving a cytogenetic or molecular remission. Prospective studies are currently investigating whether early trends in transporter expression can be used to guide treatment decisions. Plasma imatinib levels are higher in patients responding well to treatment, and may be useful in patients with suboptimal response or dubious compliance. Uptake of the second generation tyrosine kinase inhibitors, dasatinib and nilotinib, is less dependent upon hOCT1. These two drugs may therefore achieve adequate intracellular concentrations even in patients with low hOCT1 expression.
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PMID:Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia. 1839 25

The transcription factor Egr-1 is encoded by an immediate early response gene and has been shown to be a key regulator in the induction of apoptosis, mitogenesis and differentiation. It is rapidly induced by different stimuli including the glycoprotein hormone erythropoietin. In this report, we analyse the role of different erythropoietin receptor substructures for the activation of Egr-1 and the functional consequences of Egr-1 overexpression in the erythroleukemic cell line ELM-I-1. The investigation of receptor variants revealed that the activity of JAK2 and the phosphorylation of receptor tyrosine residues are essential preconditions for the ability to target Egr-1. Furthermore, we observed a close correlation of the abilities of receptors to activate the Ras-MAPK pathway and Egr-1. Using mass spectrometry we identified the Ras-GTPase-activating protein-SH3-domain-binding protein 1 (G3BP-1), a component of the Ras network of proteins, as an Egr-1 interacting protein in EPO stimulated ELM-I-1 cells. The overexpression of Egr-1 in these cells resulted in an enhanced rate of spontaneous erythroid differentiation.
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PMID:Erythropoietin receptor-mediated Egr-1 activation: structural requirements and functional implications. 1862 90

Elevated plasma concentrations of Lp(a) [lipoprotein(a)] are an emerging risk factor for atherothrombotic disease. Apo(a) [apolipoprotein(a)], the unique glycoprotein component of Lp(a), contains tandem repeats of a plasminogen kringle (K) IV-like domain. In the light of recent studies suggesting that apo(a)/Lp(a) affects endothelial function, we evaluated the effects of apo(a)/Lp(a) on growth and migration of cultured HUVECs (human umbilical-vein endothelial cells). Two full-length r-apo(a) [recombinant apo(a)] variants (12K and 17K), as well as Lp(a), were able to stimulate HUVEC growth and migration to a comparable extent; 17K r-apo(a) also decreased the levels of total and active transforming growth factor-beta secreted by these cells. Using additional r-apo(a) variants corresponding to deletions and/or site-directed mutants of various kringle domains in the molecule, we were able to determine that the observed effects of full-length r-apo(a) on HUVECs were dependent on the presence of a functional lysine-binding site(s) in the apo(a) molecule. With respect to signalling events elicited by apo(a) in HUVECs, we found that 17K treatment of the cells increased the phosphorylation level of FAK (focal adhesion kinase) and MAPKs (mitogen-activated protein kinases), including ERK (extracellular-signal-regulated kinase), p38 and JNK (c-Jun N-terminal kinase). In addition, we showed that LM609, the function-blocking antibody to integrin alphaVbeta3, abrogated the effects of 17K r-apo(a) and Lp(a) on HUVECs. Taken together, the results of the present study suggest that the apo(a) component of Lp(a) signals through integrin alphaVbeta3 to activate endothelial cells.
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PMID:Apolipoprotein(a) stimulates vascular endothelial cell growth and migration and signals through integrin alphaVbeta3. 1882 51

Interleukin-6 (IL-6) is involved in a variety of biological responses, including the glucose metabolism and cell growth, which is a critical physiological function requiring multiple metabolic pathways. Therefore, in the present study, we examined the effect of IL-6 on 2-deoxyglucose (2-DG) uptake and the related signaling pathways in primary cultured chicken hepatocytes. IL-6 increased 2-DG uptake in a time- (> or =4 h) and a dose -(> or =5 ng/ml) dependent manner. Indeed, IL-6 increased GLUT-2 mRNA and protein expression as well as 2-DG uptake, which were blocked by actinomycin D (AD, transcription inhibitor) and cycloheximide (CHX, translation inhibitor). IL-6 (10 ng/ml) increased the level of IL-6Ralpha and glycoprotein (gp) 130 (IL-6Rbeta) protein expressions. IL-6 increased Janus Kinase (JAK)-2, signal transducer and activator of transcription (STAT)-3 phosphorylation, intracellular Ca(2+) concentration, and PKC phosphorylation. IL-6-induced increase of 2-DG uptake and GLUT-2 protein expression were blocked by JAK2-specific siRNA, a STAT3 inhibitor, staurosporine, and bisindolylmaleimide I (PKC inhibitors). In addition, IL-6 increased EGFR/src/FAK, PI3K/Akt phosphorylation and 2-DG uptake as well as GLUT-2 protein expression, which were blocked by AG 1478 (EGF receptor inhibitor), PP2 (src family of tyrosine kinase inhibitor), PI3K-specific siRNA, and a Akt inhibitor. Furthermore, IL-6 increased p44/42 MAPKs phosphorylation and p44 and p42 MAPK-specific siRNA mixture blocked IL-6-induced increase of 2-DG uptake and GLUT-2 protein expression. In conclusion, IL-6 stimulates the 2-DG uptake through p44/42 MAPKs activation via Ca(2+)/PKC and EGF receptor in primary cultured chicken hepatocytes.
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PMID:Interleukin-6 promotes 2-deoxyglucose uptake through p44/42 MAPKs activation via Ca2+/PKC and EGF receptor in primary cultured chicken hepatocytes. 1900 19

Interleukin-6 (IL-6) is a pleiotropic cytokine with a pivotal role in normal hepatic growth and liver regeneration. Therefore, in the present study, we examined the effect of IL-6 on cell proliferation and the related signaling pathways in primary cultured chicken hepatocytes. IL-6 increased the level of [(3)H]thymidine incorporation in a time (>or= 6 hr)- and a dose (>or= 0.1 ng/ml)-dependent manner. Indeed, IL-6 increased the number of BrdU-positive cells and the total number of cells. IL-6 (10 ng/ml) increased the level of IL-6Ralpha and glycoprotein (gp) 130 (IL-6Rbeta) protein expression, Janus Kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, PKC, p44/42 MAPKs phosphorylation, and PPARdelta protein expression. Inhibition of each pathways blocked IL-6-induced [(3)H]thymidine incorporation increase. IL-6 increased c-fos, c-jun, and c-myc proto-oncogene mRNA levels and the percentage of cells in the S phase according to fluorescence-activated cell sorter (FACS) analysis. IL-6-induced G1/S phase progression was inhibited by AG 490 (2x10(-5) M, JAK2 inhibitor), a STAT3 inhibitor peptide (10(-5) M), bisindolylmaleimide I (10(-6) M, PKC inhibitor), PD 98059 (10(-5) M, p44/42 MAPKs blocker), or PPARdelta-specific small interfering RNAs (siRNAs). In conclusion, IL-6 stimulates the proliferation of primary cultured chicken hepatocytes through PKC, p44/42 MAPKs, and PPARdelta pathways.
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PMID:Role of interleukin-6 in the control of DNA synthesis of hepatocytes: involvement of PKC, p44/42 MAPKs, and PPARdelta. 1908 49

Interleukin-5 (IL-5) is an interdigitating homodimeric glycoprotein that is initially identified by its ability to support the in vitro growth and differentiation of mouse B cells and eosinophils. IL-5 transgenic mouse shows two predominant features, remarkable increase in B-1 cells resulting in enhanced serum antibody levels, predominantly IgM, IgA, and IgE classes and in expansion of eosinophil numbers in the blood and eosinophil infiltration into various tissues. Conversely, mice lacking a functional gene for IL-5 or IL-5 receptor alpha chain (IL-5Ralpha) display a number of developmental and functional impairments in B cells and eosinophils. IL-5 receptor (IL-5R) comprises alpha and betac chains. IL-5 specifically binds to IL-5Ralpha and induces the recruitment of betac to IL-5R. Although precise mechanisms on cell-lineage-specific IL-5Ralpha expression remain elusive, several transcription factors including Sp1, E12/E47, Oct-2, and c/EBPbeta have been shown to regulate its expression in B cells and eosinophils. JAK2 and JAK1 tyrosine kinase are constitutively associated with IL-5Ralpha and betac, respectively, and are activated by IL-5 stimulation. IL-5 activates at least three different signaling pathways including JAK2/STAT5 pathway, Btk pathway, and Ras/ERK pathway. IL-5 is one of key cytokines for mouse B cell differentiation in general, particularly for fate-determination of terminal B cell differentiation to antibody-secreting plasma cells. IL-5 critically regulates homeostatic proliferation and survival of and natural antibody production by B-1 cells, and enhances the AID and Blimp-1 expression in activated B-2 cells leading to induce mu to gamma1 class switch recombination and terminal differentiation to IgM- and IgG1-secreting plasma cells, respectively. In humans, major target cells of IL-5 are eosinophils. IL-5 appears to play important roles in pathogenesis of asthma, hypereosinophilic syndromes, and eosinophil-dependent inflammatory diseases. Clinical studies will provide a strong impetus for investigating the means of modulating IL-5 effects. We will discuss the role of IL-5 in the link between innate and acquired immune response, particularly emphasis of the molecular basis of IL-5-dependent B cell activation, allergen-induced chronic inflammation and hypereosinophilic syndromes on a novel target for therapy.
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PMID:Interleukin 5 in the link between the innate and acquired immune response. 1923 96

Cellular prion protein (PrP(c)) is a ubiquitous glycoprotein, whose physiological role is poorly characterized. It has been suggested that PrP(c) participates in neuritogenesis, neuroprotection, copper metabolism, and signal transduction. In this study we detailed the intracellular events induced by PrP(c) antibody-mediated cross-linking in PC12 cells. We found a Fyn-dependent activation of the Ras-Raf pathway, which leads to a rapid and transient phosphorylation of extracellular regulated kinases. In addition, this activation cascade relies on the engagement of integrins, and involves focal adhesion kinase activation. We demonstrated the tyrosine phosphorylation of caveolin-1 as a consequence of PrP(c) stimulation, and showed that phosphocaveolin-1 scaffolds and coordinates protein complexes involved in PrP(c)-dependent signaling. Moreover, we found that caveolin-1 phosphorylation, is a mechanism for recruiting the C-terminal Src kinase and inactivating Fyn, so as to terminate cell signaling. Furthermore our data support a significant role for PrP(c) as a response mediator in neuritogenesis and cell differentiation.
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PMID:PrPc activation induces neurite outgrowth and differentiation in PC12 cells: role for caveolin-1 in the signal transduction pathway. 1945 27

Tenascin-C is an extracellular matrix glycoprotein implicated in embryogenesis, wound healing and tumor progression. We previously revealed that tenascin-C expression is correlated with the prognosis of patients with glioblastoma. However, the exact role of endogenous tenascin-C in regulation of glioblastoma proliferation and invasion remains to be established. We show here that endogenous tenascin-C facilitates glioblastoma invasion, followed by reactive change of the surrounding brain tissue. Although shRNA-mediated knockdown of endogenous tenascin-C does not affect proliferation of glioblastoma cells, it abolishes cell migration on a two-dimensional substrate and tumor invasion with brain tissue changes in a xenograft model. The tyrosine phosphorylation of focal adhesion kinase, a cytoplasmic tyrosine kinase that associates with integrins, was decreased in tenascin-C-knockdown cells. In the analysis of clinical samples, tenascin-C expression correlates with the volume of peritumoral reactive change detected by magnetic resonance imaging. Interestingly, glioblastoma cells with high tenascin-C expression infiltrate brain tissue in an autocrine manner. Our results suggest that endogenous tenascin-C contributes the invasive nature of glioblastoma and the compositional change of brain tissue, which renders tenascin-C as a prime candidate for anti-invasion therapy for glioblastoma.
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PMID:Endogenous tenascin-C enhances glioblastoma invasion with reactive change of surrounding brain tissue. 1945 58

Reck is a membrane-anchored glycoprotein identified as a transformation suppressor. Accumulating evidence indicates that Reck negatively regulates a wide spectrum of matrix metalloproteinases and is commonly down-regulated in a variety of malignant solid tumors. Physiological cues that regulate Reck expression, however, remained unknown. In this study, we found that Reck expression was up-regulated at high cell density, low serum, or after treatment with some kinase inhibitors, such as PP2 (Src inhibitor), LY294002 (PI3-kinase inhibitor), and PF573228 (FAK inhibitor), in mouse embryo fibroblasts. Curve fitting indicated that the levels of Reck protein and Reck mRNA are quadratic in the cell density. Other factors, including serum, extracellular matrix components (type I collagen and fibronectin), the kinase inhibitors, and some of their oncogenic targets (v-Src and PIK3CA mutants), modify the shape of the quadratic curve. Comparison of these modifications implicated Src in Reck down-regulation under sparse conditions, PI3-kinase in serum-induced Reck down-regulation, and FAK in Reck down-regulation at high cell density. Fibronectin and type I collagen down-regulated Reck, supporting the role of integrin-FAK signaling in Reck down-regulation at high cell density. Our study has revealed multiple signaling pathways impinging on Reck in cultured mouse embryo fibroblasts and sets a foundation for future studies to find effective Reck inducers of potential value in cancer therapy.
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PMID:Density- and serum-dependent regulation of the Reck tumor suppressor in mouse embryo fibroblasts. 1972 Jan 43


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