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

---

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

The genetic etiology of thyroid hormone resistance syndromes is now well established. Two clinical variants, generalized resistance to thyroid hormone (GRTH) and selective pituitary resistance to thyroid hormone (PRTH), are, in most cases, caused by heterozygous mutations in the ligand-binding domain of the c-erbA beta thyroid hormone receptor gene. No human mutations have yet been described in the other related receptor gene, c-erbA alpha. In resistant patients, the mutant beta receptors act as dominant negative proteins and inhibit function of the normal beta receptor (expressed from one allele) and the normal alpha receptor (expressed from two alleles). Patients homozygous for a dominant negative allele (the Bercu patient) and without any beta receptor (the Refetoff patient) have been described. Patients with GRTH and PRTH both present with elevated free thyroxine and triiodothyronine and inappropriately normal thyroid-stimulating hormone, but the former patients are clinically euthyroid, whereas the latter patients have symptoms and signs of hyperthyroidism. However, in some cases, different patients who have been classified as having GRTH and PRTH have been found to have identical beta mutations. A recent study of the level of pituitary resistance in a large kindred with GRTH (ARG-320-HIS mutation) indicated a contributory gene in the regulation of thyroid hormone action. Relative overexpression of the mutant PRO-453-HIS receptor at the level of messenger RNA in patient fibroblasts (kindred A) was associated with short stature. Finally, an ARG-316-HIS mutation (kindred G-H) was associated with relatively weak dominant negative activity and perturbed DNA-binding properties.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Resistance to thyroid hormone in children. 795 71

Steroid Receptor Coactivator-1 (SRC-1) interacts with nuclear receptors only when they are bound to the ligands and enhance the transactivation. We identified splicing variants encoding three isoforms, SRC-1, SRC-1(-Q), and SRC-1E, generated by alternative usage of an exon(s) and splicing acceptor sites. RT-PCR analysis showed that SRC-1E was more abundantly expressed than SRC-1 or SRC-1(-Q) at the mRNA level in all the cell lines tested. SRC-1E lacks 56 amino acids of SRC-1 and has unique 14 amino acids at the carboxyl terminus, while SRC-1(-Q) differs from SRC-1 by deletion of only one glutamine residue. Since the C-terminal domain of SRC-1 has been shown to be involved in the interaction with nuclear receptors, the enhancement of transactivation by these three isoforms was tested. SRC-1E enhanced thyroid hormone dependent transactivation of reporter gene expression more profoundly than SRC-1 or SRC-1(-Q). Taken together, it was suggested that SRC-1E is the major isoform of SRC-1 to mediate thyroid hormone action.
...
PMID:A splicing variant of Steroid Receptor Coactivator-1 (SRC-1E): the major isoform of SRC-1 to mediate thyroid hormone action. 922 31

Ligand-dependent transcriptional activation by nuclear receptors is mediated by interactions with coactivators. Recently, a consensus interaction motif (LXXLL) has been identified in a number of coactivators such as steroid receptor coactivator-1 (SRC-1). SRC-1 contains three such motifs in the central (nuclear receptor binding domain-1, NBD-1) and a single one in the C-terminal (NBD-2) regions. To define the nature and role of the two NBDs in SRC-1, interaction studies between the two NBDs and thyroid hormone receptor (TR) were performed. Although NBD-1 and NBD-2 showed similar ligand- and AF-2-dependent interactions with TR in solution, these two NBDs possessed distinct interaction properties with TR when TR is bound to a thyroid hormone-response element (TRE). Both in vitro and in vivo interaction studies demonstrate that NBD-1, but not NBD-2, exhibits ligand-dependent interaction with TR in the presence of TREs. In addition, a natural isoform of SRC-1, SRC-1E, which lacks NBD-2, preserved TR as well as progesterone receptor-mediated coactivator function on reporter gene expression. Finally, we found that NBD-1 failed to interact with a TR and retinoid X receptor heterodimer complex on a transcriptionally inactive direct repeat +4 TRE in electrophoretic mobility shift assays. These observations indicate that DNA-induced, as well as ligand-induced, conformational change(s) of TR may influence the nature of its binding to SRC-1, and that the two NBDs of SRC-1 may play different roles to regulate ligand-dependent transactivation of TRs.
...
PMID:Thyroid hormone response elements differentially modulate the interactions of thyroid hormone receptors with two receptor binding domains in the steroid receptor coactivator-1. 970 85

Ligand-dependent activation of gene transcription by nuclear receptors is dependent on the recruitment of coactivators, including a family of related NCoA/SRC factors, via a region containing three helical domains sharing an LXXLL core consensus sequence, referred to as LXDs. In this manuscript, we report receptor-specific differential utilization of LXXLL-containing motifs of the NCoA-1/SRC-1 coactivator. Whereas a single LXD is sufficient for activation by the estrogen receptor, different combinations of two, appropriately spaced, LXDs are required for actions of the thyroid hormone, retinoic acid, peroxisome proliferator-activated, or progesterone receptors. The specificity of LXD usage in the cell appears to be dictated, at least in part, by specific amino acids carboxy-terminal to the core LXXLL motif that may make differential contacts with helices 1 and 3 (or 3') in receptor ligand-binding domains. Intriguingly, distinct carboxy-terminal amino acids are required for PPARgamma activation in response to different ligands. Related LXXLL-containing motifs in NCoA-1/SRC-1 are also required for a functional interaction with CBP, potentially interacting with a hydrophobic binding pocket. Together, these data suggest that the LXXLL-containing motifs have evolved to serve overlapping roles that are likely to permit both receptor-specific and ligand-specific assembly of a coactivator complex, and that these recognition motifs underlie the recruitment of coactivator complexes required for nuclear receptor function.
...
PMID:Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. 980 23

Thyroid hormone receptors (TRs) regulate transcription by recruiting distinct coregulatory complexes to target gene promoters. Coactivators implicated in ligand-dependent activation by TR include p300, the CREB-binding protein (CBP), members of the p160/SRC family, and the multisubunit TR-associated protein (TRAP) complex. Using a stable TR-expressing HeLa cell line, we show that interaction of TR with members of the p160/SRC family, CBP, and the p300/CBP-associated factor (PCAF) occurs rapidly (approximately 10 min) following addition of thyroid hormone (T3). In close agreement with these observations, we find that TR is associated with potent histone acetyltransferase activity rapidly following T3-treatment. By contrast, we observe that formation of TR-TRAP complexes occurs significantly later (approximately 3 h) post T3 treatment. An examination of the kinetics of T3-induced gene expression in HeLa cells reveals bimodal or delayed activation on specific T3-responsive promoters. Taken together, our data are consistent with the hypothesis that T3-dependent activation at specific target promoters may involve the regulated action of multiple TR-coactivator complexes.
...
PMID:Temporal formation of distinct thyroid hormone receptor coactivator complexes in HeLa cells. 1111 30

Thyroid hormone (T(3)) exerts its many biological activities through interaction with specific nuclear receptors (TRs) that function as ligand-dependent transcription factors at genes that contain a thyroid hormone response element (TRE). Mutant TRs have been detected in human hepatocellular carcinoma cell lines and tissue, but their contribution to carcinogenesis has remained unclear. The interaction of four such mutant TRs (J7-TRalpha1, J7-TRbeta1, H-TRalpha1, and L-TRalpha1) with transcriptional coregulators has now been investigated. With the exception of J7-TRalpha1, which in the absence of T(3) exhibited transcriptional silencing activity with a TRE-reporter gene construct in transfected cells, the mutant TRs had little effect (compared with that of wild-type receptors) on transcriptional activity of the reporter gene in the absence or presence of T(3), of the transcriptional corepressors SMRT, NCoR or of the transcriptional coactivator SRC. Electrophoretic mobility-shift assays revealed that, in the presence of T(3), the J7-TRss1 mutant did not interact with SRC, whereas J7-TRalpha1 and H-TRalpha1 exhibited reduced abilities to associate with this coactivator and L-TRalpha1 showed an ability to interact with SRC similar to that of wild-type TRalpha1. The dominant negative activity of the mutant TRs in transfected cells appeared inversely related to the ability of the receptors to interact with SRC. Whereas J7-TRss1, H-TRalpha1, and L-TRalpha1 did not interact with SMRT, and NCoR. J7-TRalpha1 bind to corepressors but failed to dissociate from them in the presence of T(3). These aberrant interactions between the mutant TRs and transcriptional coregulators may contribute to the highly variable clinical characteristics of human hepatocellular carcinoma.
...
PMID:Impaired interaction of mutant thyroid hormone receptors associated with human hepatocellular carcinoma with transcriptional coregulators. 1115 36

The biological effects of thyroid hormone (T3) are mediated by the thyroid hormone receptor (TR). Amphibian metamorphosis is one of the most dramatic processes that are dependent on T3. T3 regulates a series of orchestrated developmental changes, which ultimately result in the conversion of an aquatic herbivorous tadpole to a terrestrial carnivorous frog. T3 is presumed to bind to TRs, which in turn recruit coactivators, leading to gene activation. The best-studied coactivators belong to the p160 or SRC family. Members of this family include SRC1/NCoA-1, SRC2/TIF2/GRIP1, and SRC3/pCIP/ACTR/AIB-1/RAC-3/TRAM-1. These SRCs interact directly with liganded TR and function as adapter molecules to recruit other coactivators such as p300/CBP. Here, we studied the expression patterns of these coactivators during various stages of development. Amongst the coactivators cloned in Xenopus laevis, SRC3 was found to be dramatically upregulated during natural and T3-induced metamorphosis, and SRC2 and p300 are expressed throughout postembryonic development with little change in their expression levels. These results support the view that these coactivators participate in gene regulation by TR during metamorphosis.
...
PMID:Distinct expression profiles of transcriptional coactivators for thyroid hormone receptors during Xenopus laevis metamorphosis. 1472 2

The thyroid hormone receptor regulates a diverse set of genes that control processes from embryonic development to adult homeostasis. Upon binding of thyroid hormone, the thyroid receptor releases corepressor proteins and undergoes a conformational change that allows for the interaction of coactivating proteins necessary for gene transcription. This interaction is mediated by a conserved motif, termed the NR box, found in many coregulators. Recent work has demonstrated that differentially assembled coregulator complexes can elicit specific biological responses. However, the mechanism for the selective assembly of these coregulator complexes has yet to be elucidated. To further understand the principles underlying thyroid receptor-coregulator selectivity, we designed a high-throughput in vitro binding assay to measure the equilibrium affinity of thyroid receptor to a library of potential coregulators in the presence of different ligands including the endogenous thyroid hormone T3, synthetic thyroid receptor beta-selective agonist GC-1, and antagonist NH-3. Using this homogenous method several coregulator NR boxes capable of associating with thyroid receptor at physiologically relevant concentrations were identified including ones found in traditional coactivating proteins such as SRC1, SRC2, TRAP220, TRBP, p300, and ARA70; and those in coregulators known to repress gene activation including RIP140 and DAX-1. In addition, it was discovered that the thyroid receptor-coregulator binding patterns vary with ligand and that this differential binding can be used to predict biological responses. Finally, it is demonstrated that this is a general method that can be applied to other nuclear receptors and can be used to establish rules for nuclear receptor-coregulator selectivity.
...
PMID:Quantitative proteomics of the thyroid hormone receptor-coregulator interactions. 1510 Feb 13

We previously reported that thyroid hormone, 3,3',5-triiodo-l-thyronine (T3), increased Na,K-ATPase activity of adult rat alveolar epithelial cells in a transcription-independent manner via increased cell surface expression of the alpha(1) and beta(1) subunits of Na,K-ATPase. Now we sought to identify signaling molecules necessary for T3 stimulation of Na,K-ATPase activity in alveolar epithelial cells. Whereas protein kinase A inhibitor H-8 and protein kinase C inhibitor bisindolymaleimide did not block the T3-induced increase in Na,K-ATPase activity, two inhibitors of phosphoinositide 3-kinase (PI3K), wortmannin and Ly294002, and two Src kinase inhibitors, PP1 and PP2, blocked the T3-induced Na,K-ATPase activity. T3 stimulated the activity of PI3K as measured by phosphatidylinositol 3-phosphate. T3 also stimulated the serine 473 phosphorylation of the PI3K downstream molecule PKB/Akt in a dose-dependent manner. Transient expression of a constitutively active mutant of the PI3K catalytic subunit p110 augmented Na,K-ATPase activity and increased the amount of cell surface Na,K-ATPase alpha(1) subunit protein. T3 also stimulated Src family kinase activity. Transient expression of a constitutively active Src kinase increased Na,K-ATPase activity, PI3K activity, and phosphorylation of PKB/Akt at serine 473. PP1 or PP2 blocked T3-stimulated PKB/Akt phosphorylation at serine 473 and PI3K activity that was activated by an active mutant of Src; however, wortmannin did not inhibit the T3-stimulated Src kinase activity. Although PP1 and wortmannin abolished the increase in Na,K-ATPase activity induced by the active mutant of Src, PP1 did not inhibit the active mutant of PI3K-up-regulated Na,K-ATPase activity. In summary, T3 stimulates the PI3K/PKB pathway via the Src family of tyrosine kinases, and activation of both the Src family kinases and PI3K is required for the T3-induced stimulation of Na,K-ATPase activity and its cell surface expression in adult rat alveolar epithelial cells.
...
PMID:3,3',5-Triiodo-L-thyronine up-regulation of Na,K-ATPase activity and cell surface expression in alveolar epithelial cells is Src kinase- and phosphoinositide 3-kinase-dependent. 1534 23

Growth hormone (GH) is a key factor controlling postnatal growth and development. Despite growth-promoting effects in mammals, GH is not associated with muscle growth in the chicken. Janus kinase 2 (JAK2) has been identified as the first intracellular step in GH receptor (GHR) signaling in many species, however, there is limited knowledge regarding the GH signaling pathway in the chicken. In this study, GH-responsive, JAK2 immunoreactive proteins were first assessed in an avian hepatoma cell line (LMH). Tyrosine phosphorylation of a 120-122 kDa JAK2 immunoreactive protein was GH dose-dependent. In addition to in vitro studies, the timecourse of JAK2 activation in liver and skeletal muscle (Pectoralis superficialis) in response to a single intravenous (i.v.) injection of chicken GH (cGH), and the effect of chronic exposure to GH in a physiologically relevant pattern on JAK2 protein expression and tyrosine phosphorylation in vivo were assessed. At a dose of GH that was previously demonstrated to elicit a maximal metabolic response (6.25 microg/kg BW), maximum tyrosine phosphorylation of JAK2 appeared at 10 min post-GH administration in the pectoralis muscle, but was not detectable in liver. To assess whether chronic enhancement of GH would alter expression of JAK2, we utilized a dynamic model of pulsatile GH infusion that mimicked the early pattern of circulating GH expressed in younger, rapidly growing birds (high amplitude peaks with an inter-peak interval of 90 min). A 120-122 kDa protein in liver and muscle, and a dominant 130-136 kDa protein in the muscle, that was phosphorylated in response to GH, were specifically recognized by the JAK2 antibody. Chronic, pulsatile infusion of cGH into 8-week-old chickens was associated with increased abundance and tyrosine phosphorylation of JAK2 protein in both liver and muscle (P < 0.05), which were GH dose-dependent, and mirrored previously reported biological responses for the same birds [Vasilatos-Younken, R., Zhou, Y., Wang, X., McMurtry, J.P., Rosebrough, R.W., Decuypere, E., Buys, N., Darras, V.M., Van Der Geyten, S., Tomas, F., 2000. Altered chicken thyroid hormone metabolism with chronic GH enhancement in vivo: Consequences for skeletal muscle growth. Journal of Endocrinology 166, 609-620.]. In summary (1) JAK2 immunoreactive proteins that associate with the GHR and are tyrosine phosphorylated in response to GH were identified in an avian hepatoma cell line and expressed in both GH responsive (liver) and "non-responsive" (skeletal muscle) tissues; (2) tyrosine phosphorylation of JAK2 occurred within minutes of exposure to a single i.v. injection of GH in vivo in muscle but not liver of 8-week-old birds; and 3) there were GH dose-dependent increases in abundance of JAK2 protein and tyrosine phosphorylation in both tissues when chronically exposed to GH in a physiologically relevant pattern, that mirrored dose-dependent biological responses, including alterations in the pathway of thyroid hormone metabolism, previously reported. Enhanced JAK2 suggests one possible mechanism whereby chronic, physiologically appropriate exposure to the ligand enhances GH biological action via increased abundance of a key upstream component of the signal transduction pathway.
...
PMID:Regulation of JAK2 protein expression by chronic, pulsatile GH administration in vivo: a possible mechanism for ligand enhancement of signal transduction. 1599 10


1 2 3 4 Next >>

---