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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The suppressors of cytokine signaling (SOCS) family inhibits not only Janus kinase (JAK)/signal transducers and activators of transcription (STAT) but also focal adhesion kinase (FAK) signaling pathways, and has tumor suppressor activity. Aberrant methylation in the promoter region of the SOCS3 gene frequently occurs in several types of human malignancy, and its transcriptional silencing is associated with malignant tumor behavior. In malignant melanomas, the expression and methylation status of the SOCS3 gene have not been elucidated. We therefore examined the methylation status and/or protein expression of the SOCS3 gene in 5 human malignant melanoma cell lines, 2 primary cultures of normal melanocytes, and surgically resected tumors (5 malignant melanomas and 2 melanocytic nevi). Four of the 5 melanoma cell lines and the 2 primary cultures of normal melanocytes expressed SOCS3 protein to various degrees, and only one melanoma cell line was negative. Expression of SOCS3 protein was inversely correlated with methylation status in the SOCS3 promoter region, and treatment with a demethylating agent (5-aza-2'-deoxycytidine) was able to induce expression of the protein in one melanoma cell line that was SOCS3-negative and another that was weakly positive. Three of the 5 primary malignant melanomas and one of the 2 melanocytic nevi showed aberrant methylation. These results suggest that inactivation of the SOCS3 gene by hypermethylation may be involved in the promotion of malignant behavior of melanomas.
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PMID:Methylation status of the SOCS3 gene in human malignant melanomas. 1727 70

This study examined the mitogenic response of bovine peripheral T lymphocytes to leptin, a pleiotropic hormone regulating food intake and energy expenditure. Leptin alone slightly suppressed proliferation of T lymphocytes in the presence of concanavalin A (ConA). Leptin also inhibited proliferation of T lymphocytes induced by anti-CD3 antibody. ConA treatment activated some protein kinases, including p44/p42(MAPK) and Akt/PKB, while anti-CD3 antibody treatment increased mRNA expression of suppressor of cytokine signalling (SOCS) 3, interferon (IFN)gamma, interleukin (IL) 2 and IL4 in T lymphocytes. Leptin alone increased only SOCS3 mRNA expression. Simultaneous treatment with mitogens and leptin enhanced IFNgamma mRNA expression but decreased IL2 mRNA expression, without any synergistic effect on phosphorylation of protein kinases or mRNA expression of SOCS3 and IL4. These results suggest that leptin modulates bovine T lymphocyte functions.
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PMID:Leptin inhibits mitogen-induced proliferation of peripheral T lymphocytes from Holstein cows. 1744 5

Activation of the transcription factor signal transducers and activators of transcription (STAT) 3 is a defining feature of the interleukin (IL)-6 family of cytokines, which include IL-6, leukemia inhibitory factor, and cardiotrophin-1. These cytokines, as well as STAT3 activation, have been shown to be protective for cardiac myocytes and necessary for ischemia preconditioning. However, the mechanisms that regulate IL-6-type cytokine signaling in cardiac myocytes are largely unexplored. We propose that the protective character of IL-6-type cytokine signaling in cardiac myocytes is determined principally by three mechanisms: redox status of the nonreceptor tyrosine kinase Janus kinase 1 (JAK) 1 that activates STAT3, phosphorylation of STAT3 within the transcriptional activation domain on serine 727, and STAT3-mediated induction of suppressor of cytokine signaling (SOCS) 3 that terminates IL-6-type cytokine signaling. Moreover, we hypothesize that hyperactivation of the JAK kinases, particularly JAK2, mismatched STAT3 serine-tyrosine phosphorylation or heightened STAT3 transcriptional activity, and SOCS3 induction may ultimately prove detrimental. Here we summarize recent evidence that supports this hypothesis, as well as additional possible mechanisms of JAK-STAT regulation. Understanding how IL-6-type cytokine signaling is regulated in cardiac myocytes has great significance for exploiting the therapeutic potential of these cytokines and the phenomenon of preconditioning.
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PMID:Can the protective actions of JAK-STAT in the heart be exploited therapeutically? Parsing the regulation of interleukin-6-type cytokine signaling. 1770 29

Tyrosine kinase signaling is tightly controlled by negative feedback inhibitors including suppressors of cytokine signaling (SOCS). SOCS assemble as SH2 domain substrate recognition modules in ElonginB/C-cullin ubiquitin ligases. In accordance, SOCS4 reduces STAT3 signaling from EGFR through increased receptor degradation. Variable C-termini in SOCS4-SOCS7 exclude these family members from a SOCS2-type domain arrangement in which a strictly conserved C terminus determines domain packing. The structure of the SOCS4-ElonginC-ElonginB complex reveals a distinct SOCS structural class. The N-terminal ESS helix functionally replaces the CIS/SOCS1-SOCS3 family C terminus in a distinct SH2-SOCS box interface that facilitates further interdomain packing between the extended N- and C-terminal regions characteristic for this subfamily. Using peptide arrays and calorimetry the STAT3 site in EGFR (pY(1092)) was identified as a high affinity SOCS4 substrate (K(D) = 0.5 microM) revealing a mechanism for EGFR degradation. SOCS4 also bound JAK2 and KIT with low micromolar affinity, whereas SOCS2 was specific for GH-receptor.
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PMID:Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation. 1799 74

Philadelphia (Ph) chromosome-positive leukemia is characterized by the BCR/ABL1 fusion protein that affects a wide range of signal transduction pathways. The knowledge about its downstream target genes is, however, still quite limited. To identify novel BCR/ABL1-regulated genes we used global gene expression profiling of several Ph-positive and Ph-negative cell lines treated with imatinib. Following imatinib treatment, the Ph-positive cells showed decreased growth, viability, and reduced phosphorylation of BCR/ABL1 and STAT5. In total, 142 genes were identified as being dependent on BCR/ABL1-mediated signaling, mainly including genes involved in signal transduction, e.g. the JAK/STAT, MAPK, TGFB, and insulin signaling pathways, and in regulation of metabolism. Interestingly, BCR/ABL1 was found to activate several genes involved in negative feedback regulation (CISH, SOCS2, SOCS3, PIM1, DUSP6, and TNFAIP3), which may act to indirectly suppress the tumor promoting effects exerted by BCR/ABL1. In addition, several genes identified as deregulated upon BCR/ABL1 expression could be assigned to the TGFB and NFkB signaling pathways, as well as to reflect the metabolic adjustments needed for rapidly growing cells. Apart from providing important pathogenetic insights into BCR/ABL1-mediated leukemogenesis, the present study also provides a number of pathways/individual genes that may provide attractive targets for future development of targeted therapies. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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PMID:Gene expression analysis of BCR/ABL1-dependent transcriptional response reveals enrichment for genes involved in negative feedback regulation. 1818 Nov 76

Ph-negative chronic myeloproliferative disorders (CMPD) are characterized by constitutive Janus kinase-signal transducer and activator of transcription (JAK-STAT) activation. SOCS3, SOCS1 and PTPN6 (SHP1) are negative regulators of the JAK-STAT pathway. We investigated epigenetic and genetic inactivation of SOCS3, SOCS1 and PTPN6 in 112 CMPD and 20 acute myeloid leukaemia (AML) post-CMPD. SOCS3 methylation occurred at high frequency in both CMPD (46/112; 41.1%) and AML post-CMPD (10/17; 58.8%) and was associated with transcriptional silencing. In contrast, methylation of SOCS1 and PTPN6 was observed in only a fraction of CMPD (15/112, 13.4% for SOCS1; and 8/112, 7.1% for PTPN6) and AML post-CMPD (3/20, 15% for SOCS1; and 1/20, 5% for PTPN6). No somatic mutations of SOCS1 were found in CMPD. SOCS3, SOCS1 and PTPN6 methylation occurred in both JAK2V617F-positive (35.1% for SOCS3; 14.9% for SOCS1; 8.1% for PTPN6) and JAK2V617F-negative (57.1% for SOCS3; 14.3% for SOCS1; and 9.5% for PTPN6) CMPD. These data indicate that methylation of SOCS3 and, to a lesser extent, SOCS1 and PTPN6 is a frequent event in both JAK2V617F-positive and -negative CMPD and may act as an alternative or complementary mechanism to JAK2 mutations, enhancing cytokine signal transduction. The frequent inactivation of SOCS3 is a novel finding in CMPD with potential implications for the molecular pathology of these disorders.
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PMID:Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia-negative chronic myeloproliferative disorders. 1831 60

The pathogenic mechanism by which parvovirus B19 may induce inflammatory cardiomyopathy (iCMP) is complex but is known to involve inflammatory processes, possibly including activation of JAK/STAT signaling. The nonstructural B19 protein NS1 acts as a transactivator triggering signaling cascades that eventually lead to activation of interleukin 6 (IL-6). We examined the impact of NS1 on modulation of STAT signaling in human endothelial cells (HMEC-1). The NS1 sequences were identified from B19 DNA isolated from the myocardia of patients with fatal iCMP. B19 infection as well as NS1 overexpression in HMEC-1 cells produced a significant upregulation in the phosphorylation of both tyrosine(705) and serine(727) STAT3 (P < 0.05). The increased STAT3 phosphorylation was accompanied by dimerization, nuclear translocation, and DNA binding of pSTAT3. In contrast, NS1 expression did not result in increased STAT1 activation. Notably, the expression levels of the negative regulators of STAT activation, SOCS1 and SOCS3, were not altered by NS1. However, the level of PIAS3 was upregulated in NS1-expressing HMEC-1 cells. Analysis of the transcriptional activation of target genes revealed that NS1-induced STAT3 signaling was associated with upregulation of genes involved in immune response (e.g., the IFNAR1 and IL-2 genes) and downregulation of genes associated with viral defense (e.g., the OAS1 and TYK2 genes). Our results demonstrate that B19 NS1 modulates the STAT/PIAS pathway. The NS1-induced upregulation of STAT3/PIAS3 in the absence of STAT1 phosphorylation and the lack of SOCS1/SOCS3 activation may contribute to the mechanisms by which B19 evades the immune response and establishes persistent infection in human endothelial cells. Thus, NS1 may play a critical role in the mechanism of viral pathogenesis in B19-associated iCMP.
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PMID:Human parvovirus B19 NS1 protein modulates inflammatory signaling by activation of STAT3/PIAS3 in human endothelial cells. 1855 Jun 68

Inappropriate activation of JAK/STAT signaling occurs with high frequency in human cancers and is associated with cancer cell survival and proliferation. Therefore, the development of pharmacologic STAT signaling inhibitors has therapeutic potential in the treatment of human cancers. Here, we report 2-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-1-(4-nitro-phenylamino)-6-phenyl-1,2,4a,7a-tetrahydro-pyrrolo[3,4-b]-pyridine-5,7-dione (AUH-6-96) as a novel small-molecule inhibitor of JAK/STAT signaling that we initially identified through a cell-based high-throughput screening using cultured Drosophila cells. Treatment of Drosophila cells with AUH-6-96 resulted in a reduction of Unpaired-induced transcriptional activity and tyrosine phosphorylation of STAT92E, the sole Drosophila STAT homologue. In human cancer cell lines, AUH-6-96 inhibited both constitutive and interleukin-6-induced STAT3 phosphorylation. Specifically, in Hodgkin lymphoma L540 cells, treatment with AUH-6-96 resulted in reduced levels of tyrosine phosphorylated STAT3 and of the STAT3 downstream target gene SOCS3 in a dose- and time-dependent manner. In addition, AUH-6-96-treated L540 cells showed decreased expression of persistently activated JAK3, suggesting that AUH-6-96 inhibits the JAK/STAT pathway signaling in L540 cells by affecting JAK3 activity and subsequently blocking STAT3 signaling. Importantly, AUH-6-96 selectively affected cell viability only of cancer cells harboring aberrant JAK/STAT signaling. In support of the specificity of AUH-6-96 for inhibition of JAK/STAT signaling, treatment with AUH-6-96 decreased cancer cell survival by inducing programmed cell death by down-regulating the expression of STAT3 downstream target antiapoptotic genes, such as Bcl-xL. In summary, this study shows that AUH-6-96 is a novel small-molecule inhibitor of JAK/STAT signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK/STAT signaling.
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PMID:A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells. 1879 Jul 49

Homozygote individuals (HO) of the GH-transgenic zebrafish lineage (F0104), despite expressing double the amount of growth hormone (GH) in relation to the hemizygote (HE) individuals, presented smaller growth in relation to the last, and similar to the non-transgenic (NT) group. Through the analysis of the expression of genes of the somatotrophic axis in the livers of HO and NT individuals, it was verified that GHR, JAK2 and STAT5.1 did not present significant differences among the analyzed genotypes (NT and HO). However, in the IGF-I gene expression, an accentuated decrease was observed in group HO (p<0.01), suggesting a resistance effect to excess GH. This resistance could be related to the insufficient amount of energy for supporting the accelerated metabolic demand caused by excess circulating GH. Analysis of the genes involved in the regulation of GH signalization by dephosphorylation (PTP-H1 and PTP-1B) did not show any significant alteration when comparing groups HO and NT. However, the analysis of the SOCS1 and SOCS3 genes showed an induction in homozygotes of 2.5 times (p<0.01) and 4.3 times (p<0.05), respectively, in relation to non-transgenics. The results of the present work demonstrate that, in homozygotes, GH signaling is reduced by the action of the SOCS1 and SOCS3 proteins.
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PMID:SOCS1 and SOCS3 are the main negative modulators of the somatotrophic axis in liver of homozygous GH-transgenic zebrafish (Danio rerio). 1895 58

Clinical studies have shown that elevated leptin levels are an independent cardiovascular risk factor. However, little is known about the existence of platelet resistance to leptin in the setting of obesity. We examined the effects of leptin on platelet aggregation in morbidly obese subjects (n = 40; BMI, 41.6 +/- 1.1 kg/m2; leptin, 49.7 +/- 3.4 ng/ml) in comparison to normal-weight controls (n = 36; BMI, 23.3 +/- 0.4 kg/m2; leptin, 6.5 +/- 0.7 ng/ml). The aggregatory response to increasing concentrations of adenosine diphosphate (ADP) (2, 3, 4, and 5 microM) was significantly increased in platelets from obese compared to lean donors, reflecting a left shift in the dose-response curve. Plasma leptin levels, but not BMI, were significantly higher in subjects with stronger (above the median) compared to weaker (below the median) platelet aggregation at all ADP concentrations tested. In further experiments, stimulation (preincubation) with leptin (500 ng/ml) promoted ADP-induced platelet aggregation by approximately 25%, and there was no difference between platelets from obese and those from lean donors regarding the responsiveness to leptin (p = 0.99). Western blotting revealed that leptin induced phosphorylation of JAK2 and STAT3 to a similar extent in platelets from both groups. Expression of potential mediators of leptin resistance (SOCS3 and PTP1B) also did not differ in platelets from obese and control subjects. In conclusion, our data indicate that platelets from obese donors show increased aggregatory response to ADP, and that this might partly be the consequence of increased circulating leptin levels. Platelets from obese donors are not resistant to the enhancing effects of leptin on ADP-induced platelet aggregation.
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PMID:Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity. 1913 16


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