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)

Peripheral blood lymphocytes (PBL) from patients with hyperthyroidism due to Graves' disease (GD) were investigated for the ability to bind radioiodinated TSH receptor protein as hypothetical autoantigen (ABL). Thyrotropin-displacing antibody (TDA)-positive patients, who relapsed and were investigated shortly after starting antithyroid drug therapy, as well as TDA-positive patients with a first diagnosis of GD, who were investigated before starting therapy, showed significantly increased numbers of ABLs (0.2 +/- 0.17%, p less than 0.01 and 0.15 +/- 0.08%, p less than 0.001, respectively) when compared to controls (0.018 +/- 0.016%). In contrast, TDA - negative patients had no significant increase of ABLs (0.08 +/- 0.09%). Preincubation of PBLs with excess unlabelled antigen and nylon wool filtration of PBLs, reduced the number of ABLs markedly. Blocking of the binding sites on the lymphocytes with anti-Ig serum and blocking of the antigen itself by TSH depleted PBLs almost totally from ABLs. The present data indicate that: i) there are lymphocytes of B-cell characteristics capable of binding TSH-receptor; ii) there is a correlation between appearance of ABLs in hyperthyroid GD patients and the detection of TDA in patients' sera; iii) in Hashimoto, toxic nodular goiter and in some normals, a small amount of TSH receptor binding ABLs are detectable.
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PMID:Binding of solubilized human TSH-receptor protein by peripheral blood lymphocytes of patients with Graves' disease. 626 91

Apoptosis has been shown to be involved in endocrine tissue homeostasis as well as regression due to hormone deprivation. The goal of this study was to induce apoptosis and to investigate a potential role of TSH as a survival factor in thyroid follicular cells (FRTL-5) in vitro. Our results indicated that FRTL-5 cells underwent anchorage-dependent apoptosis when plated in the absence of serum and hormones, but when the cells became attached to the substrate by addition of TSH in the medium, apoptosis was prevented. The apoptosis was evaluated by positive terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling staining, typical apoptotic bodies by electron microscopy, DNA ladder by gel electrophoresis, and subdiploidy by propidium iodide-stained flow cytometry. TSH was shown to prevent apoptosis and maintain cell viability. cAMP partly mimicked this effect, which was inhibited by a specific inhibitor of protein kinase A, H-89. While investigating the mechanisms of apoptosis, we observed that the phosphorylated focal adhesion kinase was strengthened by TSH. Furthermore, FRTL-5 cells were found to undergo growth arrest in the G1 phase in the absence of TSH, accompanied by an elevated level of cyclin-dependent kinase inhibitor, p27, and a decreased level of cyclin D. In contrast, TSH promoted transition from G1 to S phase by decreasing P27 protein and increasing cyclin D expression. We concluded that in addition to regulating growth and differentiation, TSH may function as a survival factor in thyroid cells by preventing anchorage-dependent apoptosis in FRTL-5 cells partly via the cAMP pathway.
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PMID:Thyrotropin prevents apoptosis by promoting cell adhesion and cell cycle progression in FRTL-5 cells. 1057 64

TSH has multiple physiological roles: it is required for growth, differentiation, and function of the thyroid gland, and it regulates transcription of interferon-gamma (IFN-gamma)-responsive genes in thyrocytes, including genes for the major histocompatibility complex and intercellular adhesion molecule-1. This report demonstrates that TSH induces the expression of suppressor of cytokine signaling (SOCS)-1 and -3 proteins and alters the phosphorylation state of signal transducer and activator of transcription (STAT) proteins STAT1 and STAT3. The expression of SOCS-1 and SOCS-3 and the phosphorylation state of STAT1 and STAT3 were examined after treatment with TSH or IFN-gamma in either TSH-sensitive FRTL-5 thyroid cells or TSH-insensitive FRT and buffalo rat liver (BRL) cells, which lack functional TSH receptors. SOCS-1 and SOCS-3 are constitutively expressed in FRTL-5 cells, but not in FRT and BRL cells. IFN-gamma up-regulated SOCS-1 and SOCS-3 RNA and protein in FRTL-5 cells, as reported previously for nonthyroid cells. Interestingly, TSH also significantly induced SOCS-1 and SOCS-3 in FRTL-5 cells, but not in FRT and BRL cells. When SOCS-1 or SOCS-3 was overexpressed in FRTL-5 cells, STAT1 phosphorylation at Y701 and STAT1/DNA complex formation in response to IFN-gamma were reduced. Furthermore, overexpression of either SOCS-1 or SOCS-3 significantly inhibited the IFN-gamma-mediated transactivation of the rat ICAM-1 (intercellular adhesion molecule-1) promoter. TSH and IFN-gamma had different effects on STAT1 and STAT3 phosphorylation. The phosphorylation of Y701 in STAT1, which is responsible for homodimer formation, nuclear translocation, and DNA binding, was specifically stimulated by IFN-gamma, but not by TSH or forskolin. However, the phosphorylation of S727 in STAT1 was induced by IFN-gamma, TSH, and forskolin. TSH induced phosphorylation of both Y705 and S727 in STAT3, while IFN-gamma phosphorylated only the Y705. In addition, we found that SOCS-3 was associated with JAK1 and JAK2 and that these associations were stimulated by TSH. These findings demonstrate that TSH induces SOCS in thyroid cells and provides the evidence of signal cross-talk between TSH and cytokines in thyroid cells.
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PMID:Thyrotropin induces SOCS-1 (suppressor of cytokine signaling-1) and SOCS-3 in FRTL-5 thyroid cells. 1070 61

TSH is an important physiological regulator of growth and function in thyroid gland. The mechanism of action of TSH depends on interaction with its receptor coupled to heterotrimeric G proteins. We show here that TSH induces the phosphorylation of tyrosine in the intracellular kinases Janus kinase 1 (JAK1) and -2 (JAK2) in rat thyroid cells and in Chinese hamster ovary (CHO) cells transfected with human TSH receptor (TSHR). The JAK family substrates STAT3 (signal transducers and activators of transcription) are rapidly tyrosine phosphorylated in response to TSH. We also find that JAK1, JAK2, and STAT3 coprecipitate with the TSHR, indicating that the TSHR may be able to signal through the intracellular phosphorylation pathway used by the JAK-STAT cascade. TSH increases STAT3-mediated promoter activity and also induces endogenous SOCS-1 (suppressor of cytokine signaling-1) gene expression, a known target gene of STAT3. The expression of a dominant negative form of STAT3 completely inhibited TSH-mediated SOCS-1 expression. These findings suggest that the TSHR is able to signal through JAK/STAT3 pathways.
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PMID:Involvement of JAK/STAT (Janus kinase/signal transducer and activator of transcription) in the thyrotropin signaling pathway. 1080 30

The glycoprotein hormones, ACTH, TSH, FSH, and LH regulate diverse functions in endocrine cells. Although cAMP and PKA have long been shown to mediate specific intracellular signaling events including the transcription of specific genes via the CREB-CBP complex, recent observations have indicated that PKA does not account for all of the intracellular targets of cAMP. For example, TSH stimulation of thyroid cell proliferation is not completely blocked by PKA inhibitors. TSH and FSH can stimulate PKB phosphorylation by a PKAindependent but PI3-K/PDK1-dependent pathway. An FSH inducible kinase, Sgk, has recently been shown to be a close relative of PKB. Sgk is also a target of PI3-K-PDK1 pathway, indicating that some effects previously ascribed to PKB may be mediated by this inducible kinase. The identification of novel cAMP-binding proteins that exhibit guanine nucleotide exchange (GEF) activity (cAMP-GEFS; Epacs) has open new doors for cAMP action that include activation of small GTPases such as Rap1a, Rap2, and possibly Ras. These GTPases are known activators of downstream kinase cascades, including p38MAPK and Erk1/2 as well as PI3-K. Thus, FSH and TSH activation of PKB and Sgk may occur via this alternative cAMP pathway that involves cAMP-GEFs and the activation of the PI3-K/PDK1 pathway.
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PMID:New signaling pathways for hormones and cyclic adenosine 3',5'-monophosphate action in endocrine cells. 1115 28

The insulin/IGF-1/GH and p38 MAPK signaling pathways play a key role in the regulation of protein synthesis. The regulation of GH and TSH secretion hormones, that affect the activity of these pathways, plays an important role in the decline of rates of protein synthesis in aged rodent tissues. Studies have indicated that longevity of the Snell dwarf (Pit-1) mouse mutant is associated with the reduction of function of the insulin/IGF-1/GH signaling pathway. We have previously shown that PI3K activity, a signaling protein that plays a key role in the regulation of translation, is also dramatically decreased in the Snell dwarf liver suggesting that the protein synthesis-signaling pathway may be attenuated in this long-lived mouse. Similarly, signaling via p38 MAPK also plays a role in the regulation of protein synthesis. In this study we examined the activities of these signaling pathways to determine if the translation-signaling pathway is altered in young versus aged Snell dwarf mouse livers. Our data indicate that the phosphorylation and kinase activities of Akt/PKB and p38 MAPK, and the levels of phosphorylation of downstream regulators of translation are decreased in dwarf mouse livers. Thus, the overall activities of major components of the translational initiation pathway are decreased in the long-lived Snell dwarf mouse livers. We propose that down-regulation of protein synthesis may be an important characteristic of the Pit-1 mutation and longevity of the Snell dwarf mouse.
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PMID:Akt/PKB and p38 MAPK signaling, translational initiation and longevity in Snell dwarf mouse livers. 1554 73

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

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Growth hormone-insulin-like growth factor I (GH-IGF-I) system has an important role in the recovery of the central nervous system. The aim of the study was to evaluate the relationship between pituitary function (in particular, the GH-IGF-I axis) and outcome from TBI. We studied 72 patients (56 males; mean age 37.2 +/- 1.8 years) receiving rehabilitation after TBI. According to the Glasgow Coma Scale (GCS), 10 patients had moderate and 52 severe TBI. Ten patients had growth hormone GH deficiency (GHD), 10 LH-FSH, three TSH, and three ACTH deficiency. Overall pituitary dysfunction occurred in 22 (30.5%) patients, with anterior hypopituitarism in 19 (26.4%), isolated diabetes insipidus in one, and isolated hyperprolactinemia in two. GH response to GHRH + ARG (arginine) positively correlated with Functional Independence Measure (FIM D; r = 0.267, p < 0.02) and Level of Cognitive Functioning Scale (LCFS D; r = 0.287, p < 0.01) at discharge, and negatively with Disability Rating Score at discharge (DRS D; r = -0.324, p < 0.005). Unfavorable outcome measures (FIM D, LCFS D, and DRS D) occurred in patients with hypopituitarism as compared with normal pituitary function (p < 0.05). Multiple regression analysis identified both GCS (p < 0.005) and GH peak (p < 0.05) as strong independent predictors of outcome. In conclusion, recovery after TBI may be negatively influenced by concomitant pituitary dysfunction. The GH peak value is an independent predictor of outcome, indicating that recovery during an intensive rehabilitation program after TBI may be positively influenced by normal GH secretion.
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PMID:Anterior pituitary function may predict functional and cognitive outcome in patients with traumatic brain injury undergoing rehabilitation. 1800 Nov 99

The determination of the reference intervals for serum free thyroxine (FT4) and thyrotropin (TSH) is usually based on central 95 percentile intervals using subjects without detectable antibodies against thyroid peroxidase (TPO) or thyroglobulin (Tg). However, some subjects with extreme data over reference intervals are generally included. The study objective was to evaluate the reference intervals for FT4 and TSH using different outlier tests. 1,007 Japanese subjects screened based on the National Academy of Clinical Biochemistry criteria in the United States participated in this study. Serum FT4, TSH, and TPOand Tg antibodies were measured in all subjects. To make appropriate reference intervals, the Smirnov-Grubbus' outlier test was taken for antibody-free subjects (Ab[-] S-G), and the conventional outlier rejection method rejecting the value out of +/-3 standard deviation was taken for antibody-free subjects (Ab[-] STD) and all subjects (ALSTD), respectively. 12.8% of all subjects had either TPOor Tg antibodies in their serum. The 2.5(th) and 97.5(th) percentiles of reference intervals of serum FT4 (ng/dL) and TSH (mU/L) were 1.03~1.66 and 0.51 approximately 5.14 in (Ab[-] S-G), 1.03 approximately 1.65 and 0.51 approximately 4.57 in (Ab[-] STD) and 1.03 approximately 1.66 and 0.51 approximately 4.67 in (ALSTD), respectively. FT4 in males were significantly and negatively correlated with age, and TSH was significantly and positively correlated with age (P<0.000001 and P<0.00001, respectively). There was a significant difference between the sexes in FT4 (P<0.00001) but not in TSH. The prevalence of hypothyroidism, subclinical hypothyroidism, sublinical hyperthyroidism and hyperthyroidism were 0.2, 3.1, 2.3 and 0.3% (Ab[-] S-G), 0.3, 4.7, 2.3 and 0.3%(Ab[-] STD), and 0.3, 4.3, 2.3 and 0.3% (AL STD), respectively. This finding indicates that the conventional outlier rejection method is both convenient and appropriate to provide reference intervals for serum FT4 and TSH levels without regard to thyroid antibodies using large samples.
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PMID:Evaluated reference intervals for serum free thyroxine and thyrotropin using the conventional outliner rejection test without regard to presence of thyroid antibodies and prevalence of thyroid dysfunction in Japanese subjects. 1973 62

TSH is the major stimulator of thyrocyte proliferation, but its role in thyroid carcinogenesis remains unclear. To address this question, we used a mouse model of follicular thyroid carcinoma (FTC) (TRbeta(PV/PV) mice). These mice, harboring a dominantly negative mutation (PV) of the thyroid hormone-beta receptor (TRbeta), exhibit increased serum thyroid hormone and elevated TSH. To eliminate TSH growth-stimulating effect, TRbeta(PV/PV) mice were crossed with TSH receptor gene knockout (TSHR(-/-)) mice. Wild-type siblings of TRbeta(PV/PV) mice were treated with an antithyroid agent, propylthiouracil, to elevate serum TSH for evaluating long-term TSH effect (WT-PTU mice). Thyroids from TRbeta(PV/PV)TSHR(-/-) showed impaired growth with no occurrence of FTC. Both WT-PTU and TRbeta(PV/PV) mice displayed enlarged thyroids, but only TRbeta(PV/PV) mice developed metastatic FTC. Molecular analyses indicate that PV acted, via multiple mechanisms, to activate the integrins-Src-focal adhesion kinase-p38 MAPK pathway and affect cytoskeletal restructuring to increase tumor cell migration and invasion. Thus, growth stimulated by TSH is a prerequisite but not sufficient for metastatic cancer to occur. Additional genetic alterations (such as PV), destined to alter focal adhesion and migration capacities, are required to empower hyperplastic follicular cells to invade and metastasize. These in vivo findings provide new insights in understanding carcinogenesis of the human thyroid.
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PMID:Growth activation alone is not sufficient to cause metastatic thyroid cancer in a mouse model of follicular thyroid carcinoma. 2013 53


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