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)

Some biochemical events following the binding of prolactin (PRL) to its receptor in normal human leukocytes were investigated. PRL enhanced JAK2 phosphorylation in peripheral blood mononuclear cells (PBMC) but not in granulocytes. PRL also induced phosphorylation of Stat-5 in PBMC and Stat-1 in granulocytes. Subsequent binding of Stat-5- and of Stat-1-like molecules to a GAS responsive element from the beta-casein promoter was detected by EMSA. p38 MAPK (but not p42/p44 MAPK) was activated by PRL in both leukocyte populations. PRL induced iNOS and CIS mRNA expression in granulocytes. Increased expression of IRF-1 and SOCS-2 was observed in granulocytes and of SOCS-3 and iNOS in PBMC. Similar effects were obtained with ovine and human PRL. Antiserum to PRL reduced iNOS and IRF-1 expression induced by PRL in granulocytes and reduced iNOS expression in PBMC. Also, pretreatment of granulocytes with a p38 MAPK inhibitor (SB 203580) prevented in part PRL-induced iNOS and IRF-1 expression. In PBMC, the p38 inhibitor decreased PRL-induced iNOS gene expression. These results indicate that PRL-induced gene regulation in leukocytes requires the activation of at least two different pathways: the Stat and the MAP kinase pathways. Moreover, although PRL activates Stat in both leukocyte types, signal transduction is different in granulocytes and in PBMC. Most importantly, PRL modulates the expression of genes crucial to leukocyte function. The present findings reinforce the concept that PRL has "cytokine-like" activity in human leukocytes.
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PMID:Cytokine-like effects of prolactin in human mononuclear and polymorphonuclear leukocytes. 1169 20

Inhibition of PRL hormone signaling by suppressor of cytokine signaling (SOCS)/cytokine-inducible SH2-containing protein (CIS) was investigated in transfected HEK 293 cells. We used the physiologically relevant wild-type beta-casein promoter as a target gene for PRL action. We demonstrate that CIS produces a 70% inhibition of PRL signaling by a mechanism distinct from, and downstream of, the effect of SOCS-1 on JAK2. This inhibition involves association with the PRL receptor (PRLR), resulting in the inhibition of signal transducer and activator of transcription 5 (STAT5) activation. Further, we show that SOCS-3 coimmunoprecipitates with the PRLR. These data suggest that SOCS-3 involves a second pathway for the inhibition of PRL signaling other than JAK2 inhibition. Additional results indicate that SOCS-2 can play a more important potentiator role on PRL signaling, resulting in a restoration of 50% of transcriptional inhibition induced by SOCS-3 and a restoration of 100% of transcriptional inhibition induced by CIS. SOCS-2 was able to block the inhibitory effect of SOCS-1. These results indicate that SOCS-2 seems to be an antagonist of the other SOCS. SOCS-1 binds JAK2 and inhibits its phosphorylation; SOCS-3 does not bind JAK2 but binds the PRLR that may mediate its inhibition of JAK2; and finally, CIS binds the PRLR but inhibits signal transducer and activator of transcription 5 rather than JAK2.
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PMID:Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor. 1171 28

The effects of continuous high GH levels on GH signal transduction through the GH receptor (GHR)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) pathway as well as the desensitization of this pathway by suppressors of cytokine signaling (SOCS) were studied in transgenic mice overexpressing GHRH. In transgenic mice, hepatic GHR levels were 4.5-fold higher than in normal animals, whereas the protein contents of JAK2, STAT5a, and STAT5b did not vary. This same pattern was found for basal tyrosine phosphorylation (PY-): PY-GHR was 4.5-fold increased in transgenic mice, whereas there were no differences in PY-JAK2 and PY-STATs between normal and transgenic animals. After GH administration, tyrosine phosphorylation of GHR, JAK2, and STAT5s increased 3- to 7-fold in normal mice, but no significant changes were found in transgenic mice, indicating a decreased GH sensitivity in these animals. The content of cytokine-inducible SH2 protein, a member of the SOCS family, was 18-fold higher in GHRH-transgenic than in normal mice. Conversely, SOCS-3, present in normal mice, was hardly seen in transgenic animals, whereas SOCS-2 levels did not vary. These findings suggest that cytokine-inducible SH2 protein, significantly induced by continuously elevated GH levels, may be the SOCS protein responsible for the GH signaling desensitization in transgenic animals.
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PMID:Cytokine-inducible SH2 protein up-regulation is associated with desensitization of GH signaling in GHRH-transgenic mice. 1179 90

Constitutive activation of the BCR-ABL tyrosine kinase is fundamental to the pathogenesis of chronic myeloid leukemia (CML). STI571 inhibits this activity and modulates the transcription of several genes. It was shown by differential display that the suppressor of cytokine signaling-2 (SOCS-2) gene was down-regulated by STI571 treatment in 14 of 16 BCR-ABL-positive cell lines and in 2 BCR-ABL-transfected murine lines, but not in BCR-ABL-negative counterparts. The effect was maximal at 2 hours and persisted for at least 24 hours after exposure to 1 microM STI571, whereas SOCS-1 and SOCS-3 expression were unaffected. Baseline levels of SOCS-2 were significantly higher in BCR-ABL-positive as compared with BCR-ABL-negative cell lines. It was similar in leukocytes and CD34(+) cells from healthy persons (n = 44) and patients with CML in chronic phase (CP; n = 60) but significantly increased in patients with CML in blast crisis (BC; n = 20) (P <.0001). Mononuclear cells (MNCs) from 3 of 4 patients with CML in BC showed a 2-fold to 12-fold down-regulation of SOCS-2 levels on in vitro exposure to STI571; moreover, a 2-fold to 11-fold decrease in SOCS-2 was observed in MNCs from 7 of 8 patients with CML in BC who responded to treatment with STI571. Refractoriness to STI571 or relapse after initial response was accompanied by augmentation of SOCS-2 expression. Ectopic overexpression of SOCS-2 in 32Dp210 cells slowed growth, inhibited clonogenicity, and increased their motility and sensitivity to STI571. Overall, the results suggest that SOCS-2 is a component of a negative feedback mechanism; it is induced by Bcr-Abl but cannot reverse its overall growth-promoting effects in blastic transformation.
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PMID:Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism. 1186 Dec 94

Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
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PMID:Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. 1255 91

One of the long-term effects of growth hormone (GH) in adipocytes is to maintain a state of refractoriness to insulin-like effects, a refractoriness which otherwise declines within a few hours of GH starvation. Here, we examined differences in GH signaling and the possible role for the recently identified family of suppressors of cytokine signaling (SOCS) proteins in the transition between the refractory and the responsive states in rat adipocytes. The ability of GH to stimulate lipogenesis and tyrosine phosphorylation of the GH receptor (GHR), Janus kinase 2 (Jak2), insulin receptor substrate-1 (IRS-1) and -2 (IRS-2) was greatly reduced in refractory as compared to responsive primary rat adipocytes. However, phosphorylation of Signal Transducer and Activator of Transcription 5 (Stat5) was not affected. SOCS-3 and CIS mRNA levels were significantly higher in refractory compared to responsive cells and could be induced by GH, whereas the level of SOCS-2 mRNA was unchanged. With overexpression of GHR, Jak2 and IRS-1 along with each of these SOCS proteins in human A293 cells, we could demonstrate that both SOCS-1 and SOCS-3 completely inhibited the GH-stimulated tyrosine phosphorylation of IRS-1, whereas SOCS-2 and CIS did not. Our data suggest that GH induces refractoriness to the insulin-like effects in a negative-feedback manner by inhibiting GH-induced GHR/Jak2/IRS-1/IRS-2 phosphorylation through upregulation of SOCS-3, which almost completely blocks Jak2 activation.
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PMID:SOCS-3 is involved in the downregulation of the acute insulin-like effects of growth hormone in rat adipocytes by inhibition of Jak2/IRS-1 signaling. 1273 78

To investigate the influence of chronic GH deficiency on GH signaling in vivo, we have analyzed Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT) 5 GH signaling pathway, and its regulation by the suppressors of the cytokine signaling SOCS and by the JAK2-interacting protein SH2-Bbeta, in liver of Ames dwarf (Prop1df/Prop1df) mice, which are severely deficient in GH, prolactin and TSH, and of their normal littermates. Prop1df/Prop1df mice displayed unaltered GH receptor, JAK2 and STAT5a/b protein levels. No significant differences in the basal tyrosine-phosphorylation levels of JAK2 and STAT5a/b were found between both groups of animals. After in vivo administration of a high GH dose (5 microg/g body weight (BW)), the tyrosine-phosphorylation levels of JAK2 and STAT5a/b increased significantly, reaching similar values in normal and dwarf mice. However, after stimulation with lower GH doses (50 and 15 ng/g BW) the tyrosine-phosphorylation level of STAT5a/b was higher in dwarf mice. The protein content of CIS, a SOCS protein that inhibits STAT5 signaling, was approximately 80% lower in dwarf mice liver, while SOCS-2 and SOCS-3 levels were unaltered. The content of SH2-Bbeta, a modulator of JAK2 activity, was reduced by approximately 30% in dwarf mice, although this was associated with normal JAK2 response to a high GH dose. In summary, Prop1df/Prop1df mice display increased hepatic sensitivity to GH, an effect that could be related to the lower abundance of CIS in this tissue. Furthermore, the lower CIS content found in this model of GH deficiency suggests that CIS protein levels are regulated by GH in vivo.
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PMID:Increased sensitivity to GH in liver of Ames dwarf (Prop1df/Prop1df) mice related to diminished CIS abundance. 1642 18

Activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) pathway by GH is terminated by the suppressors of cytokine signaling (SOCSs) and protein tyrosine phosphatases, Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 and SHP-2. Based on our recent report that estrogen inhibits GH signaling by stimulating SOCS-2 expression, we investigated the effects of selective estrogen receptor modulators (SERMs) on GH signaling in human embryonic kidney (HEK293) and breast cancer (MDA-MB-231) cells expressing human GH receptor and estrogen receptor-alpha. 17beta-estradiol (E(2)) suppressed GH activation of a STAT5-responsive luciferase reporter and JAK2 phosphorylation in both cell models. 4-hydroxytamoxifen and raloxifene augmented these actions of GH in HEK293 cells but not breast cancer cells. SOCS-2 expression in both cell types was stimulated by E(2) but unaffected by SERMs. In HEK293 cells, SHP-1 was inhibited by raloxifene and 4-hydroxytamoxifen, whereas the latter additionally inhibited SHP-2. The phosphatases were unaffected by E(2). In breast cancer cells, phosphatase activity was not altered by SERMs or E(2). In summary, estrogen inhibited the JAK2/STAT5 signaling of GH and stimulated SOCS-2 expression in both HEK293 and breast cancer cells. By contrast, SERMs augmented GH signaling by reducing SHP activities in HEK293 cells and had no effect on both in breast cancer cells. We provide the first evidence for a novel mechanism regulating GH signaling, in which SERMs enhance GH activation of the JAK2/STAT5 pathway in a cell-type-dependent manner by attenuating protein tyrosine phosphatase activities.
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PMID:Regulation of growth hormone signaling by selective estrogen receptor modulators occurs through suppression of protein tyrosine phosphatases. 1727 97

Growth hormone (GH) binding to a membrane receptor dimer triggers multiple intracellular signaling pathways. Signal transducers and activators of transcription are the most relevant of these pathways for GH action. GH also activates several inhibitory mechanisms, particularly suppressors of cytokine signaling (SOCS/CIS) proteins. GH-overexpressing mice exhibit hepatic desensitization of the JAK2/STAT5 GH-signaling pathway, associated with an increased abundance of CIS. Vitamin D3 has been shown to inhibit GH-induced expression of CIS and SOCS-3 and therefore prolong GH signaling in osteoblast-like cells. The purpose of the present study is to determine if vitamin D3 could attenuate CIS expression in GH-overexpressing mice, and consequently allow GH JAK2/STAT5 signaling in GH-responsive tissues in these animals. The abundance of CIS, SOCS-2, SOCS-3, STAT5b and GHR, as well as STAT5b tyrosine phosphorylation after a GH stimulus, were measured in liver and muscle of GHRH-transgenic mice treated with 1alpha,25-dihydroxyvitamin D3 for 7 days. This treatment did not diminish CIS expression in GH-overexpressing mice tissues, nor did the content of SOCS-2 and SOCS-3 significantly vary. GH-induced STAT5b phosphorylation levels were similar to basal values in transgenic mice liver treated with or without vitamin D; the refractoriness to GH was also present in muscle. Therefore, treatment with vitamin D was not sufficient to revert STAT5 GH signaling desensitization in non-calcemic tissues in GH-overexpressing mice.
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PMID:Vitamin D3 cannot revert desensitization of growth hormone (GH)-induced STAT5-signaling in GH-overexpressing mice non-calcemic tissues. 1788 Dec 71

Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Three SOCS genes, SOCS-1, 2 and 3, have been identified and their sequences analyzed in an economically important fish, rainbow trout (Oncorhynchus mykiss, Walbaum). In general, these three SOCS molecules are well conserved especially in the SRC homology 2 and the SOCS domains, with sequence identities between trout and mammals ranging from 41 to 42, 50 to 51, and 58 to 61% for SOCS-1, 2 and 3, respectively. The identities within fish species are slightly higher, with sequence identities between trout and the other fish species at 44-46, 64-70, and 71-76% for SOCS-1, 2 and 3, respectively. All the SOCS-1, as well as all the SOCS-2 or 3 molecules from different species are grouped together in phylogenetic tree analysis with high bootstrap support, with the fish molecules in each type grouping closely together. The expression of the trout SOCS-1, 2 and 3 genes are detectable by real-time PCR in all the eight tissues studied; the gills, skin, muscle, liver, spleen, head kidney, intestine and brain. SOCS-1 is highly expressed in intestine, head kidney, spleen, gills and skin. SOCS-2 is highly expressed in brain, head kidney, muscle, spleen, gills, skin and intestine. The expression of SOCS-3 is the highest among the three SOCS genes in all the tissues except in intestine, brain and liver. The modulation of SOCS gene expression is shown to be cytokine and cell type dependent. While interferon-gamma up-regulates the expression of all the three SOCS genes in both the fibroid RTG-2 and the monocyte/macrophage RTS-11 cell lines, interleukin-1beta only up-regulates SOCS gene expression in the RTG-2 cell line, with little, if any, effect in the RTS-11 cell line.
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PMID:Rainbow trout suppressor of cytokine signalling (SOCS)-1, 2 and 3: molecular identification, expression and modulation. 1792 Jan 26


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