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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PACT, the protein activator of the double-stranded (ds)RNA-activated protein kinase (PKR) has been shown to strongly interact with and activate PKR in cultured cells and in vitro. To further analyze the functions of PACT we have recently generated PACT knockout (KO) mice and described several developmental defects that are absent in PKR KO mice. Importantly, PACT has been previously suggested to be involved in different signaling pathways that include endoplasmic reticulum stress, serum deprivation, growth factor withdrawal, viral infection, and cytokine responses. In this study, we have analyzed the contribution of PACT to these pathways using cells derived from wildtype (WT) and PACT KO mice. Notably, we have been unable to detect any significant differences in the responses to stress stimuli comparing WT and PACT KO cells, although we have been able to validate the specific interaction between PACT and PKR. Taken together, our results reinforce the importance of genetic loss of function analysis to infer protein function.
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PMID:The role of PACT in mediating gene induction, PKR activation, and apoptosis in response to diverse stimuli. 1872 37

How cyclic AMP (cAMP) could positively or negatively regulate G1 phase progression in different cell types or in cancer cells versus normal differentiated counterparts has remained an intriguing question for decades. At variance with the cAMP-dependent mitogenesis of normal thyroid epithelial cells, we show here that cAMP and cAMP-dependent protein kinase activation inhibit S-phase entry in four thyroid carcinoma cell lines that harbor a permanent activation of the Raf/ERK pathway by different oncogenes. Only in Ret/PTC1-positive TPC-1 cells did cAMP markedly inhibit the Raf/ERK cascade, leading to mTOR pathway inhibition, repression of cyclin D1 and p21 and p27 accumulation. p27 knockdown did not prevent the DNA synthesis inhibition. In the other cells, cAMP little affected these signaling cascades and levels of cyclins D or CDK inhibitors. However, cAMP differentially inhibited the pRb-kinase activity and T172-phosphorylation of CDK4 complexed to cyclin D1 or cyclin D3, whereas CDK-activating kinase activity remained unaffected. At variance with current conceptions, our studies in thyroid carcinoma cell lines and previously in normal thyrocytes identify the activating phosphorylation of CDK4 as a common target of opposite cell cycle regulations by cAMP, irrespective of its impact on classical mitogenic signaling cascades and expression of CDK4 regulatory partners.
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PMID:Cyclic AMP inhibits the proliferation of thyroid carcinoma cell lines through regulation of CDK4 phosphorylation. 1879 15

The TAR RNA binding Protein, TRBP, inhibits the activity of the interferon-induced protein kinase R (PKR), whereas the PKR activator, PACT, activates its function. TRBP and PACT also bind to each other through their double-stranded RNA binding domains (dsRBDs) and their Medipal domains, which may influence their activity on PKR. In a human immunodeficiency virus (HIV) long terminal repeat-luciferase assay, PACT unexpectedly reversed PKR-mediated inhibition of gene expression. In a translation inhibition assay in HeLa cells, PACT lacking the 13 C-terminal amino acids (PACTDelta13), but not full-length PACT, activated PKR and enhanced interferon-mediated repression. In contrast, in the astrocytic U251MG cells that express low TRBP levels, both proteins activate PKR, but PACTDelta13 is stronger. Immunoprecipitation assays and yeast two-hybrid assays show that TRBP and PACTDelta13 interact very weakly due to a loss of binding in the Medipal domain. PACT-induced PKR phosphorylation was restored in Tarbp2(-/-) murine tail fibroblasts and in HEK293T or HeLa cells when TRBP expression was reduced by RNA interference. In HEK293T and HeLa cells, arsenite, peroxide, and serum starvation-mediated stresses dissociated the TRBP-PACT interaction and increased PACT-induced PKR activation, demonstrating the relevance of this control in a physiological context. Our results demonstrate that in cells, TRBP controls PACT activation of PKR, an activity that is reversed by stress.
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PMID:TRBP control of PACT-induced phosphorylation of protein kinase R is reversed by stress. 1893 60

Cellular stresses such as disruption of calcium homeostasis, inhibition of protein glycosylation, and reduction of disulfide bonds result in accumulation of misfolded proteins in the endoplasmic reticulum (ER) and lead to cell death by apoptosis. Tunicamycin, which is an inhibitor of protein glycosylation, induces ER stress and apoptosis. In this study, we examined the involvement of double-stranded RNA (dsRNA)-activated protein kinase (PKR) and its protein activator PACT in tunicamycin-induced apoptosis. We demonstrate for the first time that PACT is phosphorylated in response to tunicamycin and is responsible for PKR activation by direct interaction. Furthermore, PACT-induced PKR activation is essential for tunicamycin-induced apoptosis, since PACT as well as PKR null cells are markedly resistant to tunicamycin and show defective eIF2alpha phosphorylation and C/EBP homologous protein (CHOP, also known as GADD153) induction especially at low concentrations of tunicamycin. Reconstitution of PKR and PACT expression in the null cells renders them sensitive to tunicamycin, thus demonstrating that PACT-induced PKR activation plays an essential function in induction of apoptosis.
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PMID:Essential role of PACT-mediated PKR activation in tunicamycin-induced apoptosis. 1900 93

A 29 yrs-old patient was referred to our hospital due to generalized convulsions. She had hyperthyroidism treated with methimazole. Her MRI showed 4 metastatic lesions in the brain. She had a goiter with a "cold" nodule and a palpable ipsilateral lymph node. The FNAB disclosed a papillary thyroid carcinoma. Under 5 mg of MMI treatment, she had a subclinical hyperthyroidism and TRAb were 47.8% (n.v. < 10%). The CT scan also showed lung metastasis. She underwent a total thyroidectomy with a modified neck dissection and she received an accumulated radioiodine dose of 700 mCi during the following two years. She died from the consequences of multiple metastatic lesions. Studies were performed in DNA extracted from paraffin-embedded tissue from the tumor, the metastatic lymph node and the non-tumoral thyroid. The genetic analysis of tumoral DNA revealed point mutations in two different genes: the wild type CAA at codon 61 of N-RAS mutated to CAT, replacing glycine by histidine (G61H) and the normal GCC sequence at codon 623 of the TSHR gene was replaced by TCC, changing the alanine by serine (A623S). In the non-tumoral tissue no mutations were found. In vitro studies showed a constitutive activation of the TSHR. It is very probable that this activating mutation of the TSHR is unable to reach the end point of the PKA cascade in the tumoral tissue. One possibility that could explain this is the presence of a cross-signaling mechanism generating a deviation of the TSH receptor cascade to the more proliferative one involving the MAPKinase, giving perhaps a more aggressive behavior of this papillary thyroid cancer.
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PMID:Fatal outcome of a young woman with papillary thyroid carcinoma and graves' disease: possible implication of "cross-signalling" mechanism. 1908 10

The dsRNA binding protein (DRBP) family comprise one or more evolutionarily conserved dsRNA-binding domains (DRBD) of approximately 65-68 amino acids, are found in both eukaryotes and prokaryotes and are even encoded by plants and viruses. DRBP's do not recognize specific nucleotide sequences and primarily interact with approximately 11-16 base pairs present within A-form double helix RNAs, which can include ssRNA's with extensive secondary structure. The DRBP family include TRBP (TAR RNA binding protein), PKR (protein kinase activated by dsRNA), PACT (Protein Activator of PKR), ADAR (Adenosine deaminases acting on RNA), and the RNase III family including DICER, which collectively play important roles in mRNA elongation, RNA interference (RNAi), mRNA editing, stability, splicing and/or export and translation. Here, we focus on the role of DRBP's referred to as the NFARs (Nuclear Factors associated with dsRNA) which are translated from two major alternatively spliced products encoded from a single gene. Evidence indicates that the NFAR proteins play crucial roles in mRNA post-transcriptional regulation, including mRNA stability, export and translation and may also have an important function in host defense.
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PMID:The NFAR's (nuclear factors associated with dsRNA): evolutionarily conserved members of the dsRNA binding protein family. 1910 22

RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the beta-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal-regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3beta (GSK3beta) phosphorylation, thereby reducing GSK3beta-mediated NH(2)-terminal beta-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with beta-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)beta-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3beta complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP-responsive element binding protein (CREB) phosphorylation and promotes the formation of a beta-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing beta-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC-expressing cells. Silencing of beta-catenin by small interfering RNA inhibits proliferation of RET/PTC-transformed PC Cl3 thyrocytes, whereas a constitutively active form of beta-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on beta-catenin to stimulate cell proliferation.
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PMID:The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation. 1922 51

PACT is a double-stranded RNA-binding protein that also binds and activates the latent protein kinase, PKR, which plays a major role in cellular antiviral defense in mammals. For evaluating PACT's contribution to the innate immune system, Pact(-/-) mice have been generated; these mice exhibit notable developmental abnormalities including microtia, with craniofacial, ear, and hearing defects. Here we report that, in addition, Pact(-/-) mice had smaller body size and fertility defects, both of which were caused by defective pituitary functions. Pact(-/-) mice exhibited anterior pituitary lobe (AL) hypoplasia, which developed postnatally, when the second phase of pituitary expansion occurs. Among the 5 cell types in AL, the numbers of corticotrophs, gonadotrophs, and somatotrophs were equally decreased in Pact(-/-) mice with a greater impact on lactotrophs and a lesser impact on thyrotrophs. PACT mRNA and protein were highly expressed in the pituitary of wild-type (Wt) mice during the postnatal wave of AL proliferation, the same period in which the hypoplasia developed in Pact(-/-) mice. During this time, the pituitaries of Pact(-/-) mice did not exhibit significantly increased apoptosis compared with Wt mice but showed a decrease in cell proliferation. The inhibition of cell proliferation observed in vivo could be recapitulated in vitro in GH3 somato/lactotroph and LbetaT2 gonadotroph cell lines; knockdown of PACT expression with siRNA diminished the rate of proliferation of these cells. Our study revealed a physiologically significant role for PACT in cell proliferation and an essential role of a dsRNA-binding protein in mammalian pituitary expansion.
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PMID:The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation. 1954 53

Many extracellular stresses cause inhibition of translation initiation by triggering phosphorylation of the initiation factor, eIF-2alpha. A major protein kinase responsible for this phosphorylation is PKR, a latent kinase which itself needs to be activated by autophosphorylation. In stressed cells, this activation occurs when PACT, a PKR-binding protein, is phosphorylated and activates PKR. We have previously demonstrated that the presence of specific residues in domain 3 of PACT is necessary for its ability to activate PKR in vivo. Here, we analyze the biochemical properties of the inactive PACT mutants by assessing their ability to bind and activate PKR in vitro. Among the essential residues, two serines need to be phosphorylated in vivo for PACT's ability to activate PKR. We substituted those serines with aspartic acids, mimics of phosphoserines, and investigated the properties of the corresponding mutant PACTs. In vitro, they activate PKR more efficiently because they bind to PKR more tightly. These results indicate that stress-induced phosphorylation of specific serine residues in domain 3 of PACT increases its affinity for PKR, which leads to better activation of PKR and resultant eIF-2alpha phosphorylation.
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PMID:Biochemical analysis of PKR activation by PACT. 1958 Mar 24

Papillary thyroid cancer (PTC) is the most common endocrine malignancy, accounting for 85-90% of all thyroid cancers. Genetic alternations involving the mitogen-activated protein kinase (MAPK) pathway are frequently demonstrated in PTC, such as RET/PTC, RAS, and B-type Raf kinase (BRAF) mutations. Over 90% of BRAF mutations are T1799A, resulting in a BRAF(V600E) mutation. BRAF(V600E) is present in approximately 50% of PTC and also found in aggressive histologic variants and PTC-derived anaplastic thyroid cancer, but is rare in follicular variants, and not found in follicular thyroid cancer. The tumorigenic role of BRAF(V600E) in the development of PTC was documented in thyroid-targeted BRAF(V600E) transgenic mice, and rat thyroid cells overexpressed with BRAF(V600E) suggested that BRAF(V600E) is an initiator of tumorigenesis and is required for tumor progression in PTC. Most clinical studies have demonstrated an association of BRAF(V600E) mutation with aggressive clinicopathologic characteristics and high tumor recurrence, although the results are controversial. The association is also observed in patients with papillary thyroid microcarcinomas and low-risk PTC. As a highly specific and unique mutation in PTC, testing for BRAF(V600E) in fine-needle aspiration specimens has been shown to refine the diagnostic accuracy of PTC in indeterminate cytology. Preoperative BRAF(V600E) analysis in low-risk patients may provide important value for prognostication, and these patients might benefit from receiving more intensive management and frequent follow-up. BRAF-targeted therapies have been developed to treat various human cancers including advanced thyroid cancers. Preclinical results are encouraging, but the anticancer effects of clinical trials are disappointing. Studies of multi-kinase inhibitors and/or combination with other regimens are underway in the treatment of advanced thyroid cancers. In this article, we review the pathogenesis of PTC, and the clinical implications of BRAF(V600E) mutation in the diagnosis, prognosis and potential targeted therapeutic strategies for thyroid cancers.
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PMID:BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. 2023 Sep 95


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