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)

Supraphysiological levels of glucocorticoids, whether endogenous (Cushing's syndrome) or exogenous (glucocorticoid therapy), inhibit growth in children and immature animals. This effect has long been suspected to be due to glucocorticoid antagonism of GH action at the level of peripheral tissues. In the present study we demonstrate direct antagonism of GH action at the cellular level by the artificial glucocorticoid dexamethasone. Dexamethasone was found to inhibit the ability of GH to elicit several early events in GH signaling in 3T3-F442A fibroblasts. Dexamethasone (100 nM) for 24 h decreases by 50-75% GH-induced tyrosyl phosphorylation of mitogen-activated protein kinases ERK1 and ERK2, the transcription factor Stat3/APRF, the GH receptor-associated tyrosine kinase JAK2, and the GH receptor. These effects appear to be specific to GH. Dexamethasone does not inhibit induction of tyrosyl phosphorylation of ERK proteins by epidermal growth factor or phorbol myristate acetate, nor does it block induction of tyrosyl phosphorylation of Stat3/APRF by leukemia inhibitory factor or interleukin-6, or induction of JAK2 by leukemia inhibitory factor or interferon-gamma. Dexamethasone does not decrease the expression of ERK1 or -2, Stat3, or JAK2 proteins. Rather, the effects of dexamethasone on GH action appear to be due to a decrease in the number of GH receptors in the plasma membrane. Twenty-four-hour treatment with dexamethasone leads to a 50% decrease i GH binding, which Scatchard analysis suggests is due to a decrease in GH receptor number. These findings suggest that glucocorticoids antagonize cellular GH action by decreasing GH binding, suggesting a mechanism by which systemic glucocorticoids could antagonize GH action in peripheral tissues.
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PMID:Dexamethasone-induced antagonism of growth hormone (GH) action by down-regulation of GH binding in 3T3-F442A fibroblasts. 758 9

We investigated in vitro effects of recombinant human thrombopoietin (TPO), or c-Mpl ligand, on human platelets. TPO induced rapid dose-dependent tyrosine phosphorylation of several proteins. We identified Janus tyrosine kinases, Tyk2 and JAK2, and a member of STAT (signal transducers and activators of transcription) family, STAT3, as the tyrosine-phosphorylated proteins in response to TPO. TPO by itself did not cause platelet aggregation and shape change, but augmented ADP-induced aggregation in a dose-dependent manner. Acetylsalicylic acid inhibited the secondary aggregation enhanced by TPO, but not the TPO-induced potentiation of the primary aggregation. TPO modulates platelet activation possibly through protein-tyrosine phosphorylation.
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PMID:Thrombopoietin, c-Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists-induced aggregation in platelets in vitro. 758 10

Chinese hamster ovary (CHO) cells, stably transfected with the long form of the prolactin (PRL) receptor (PRL-R) cDNA, were used for PRL-R signal transduction studies. Patch-clamp technique in whole cell and cell-free configurations were employed. Exposure of transfected CHO cells to 5 nM PRL led to the increase of Ca(2+)- and voltage-dependent K+ channel (KCa) activity. The effect was direct as it was observed also in excised patch experiments. A series of tyrosine kinase inhibitors was studied to investigate the possible involvement of protein tyrosine kinases in KCa functioning and its stimulation by PRL. Genistein, lavendustin A, and herbimycin A decreased in a concentration and time-dependent manner the amplitude of the KCa current in whole cell and the open probability of KCa channels in cell-free experiments. The subsequent application of PRL was ineffective. The protein tyrosine phosphatase inhibitor orthovanadate (1 mM) stimulated KCa channel activity in excised patches, indicating that channels can be modulated in opposite directions by protein tyrosine kinase and protein tyrosine phosphatase. Moreover, in whole cell experiments as well as in excised patch recordings, anti-JAK2 tyrosine kinase antibody decreased the KCa conductance and the open probability of the KCa channels. Subsequent application of PRL was no longer able to stimulate KCa conductance. Immunoblotting studies using the same anti-JAK2 antibody, revealed the constitutive association of JAK2 kinase with PRL-R. Preincubation of anti-JAK2 antibody with the JAK2 Immunizing Peptide abolished the effects observed using anti-JAK2 antibody alone in both electrophysiological and immunoblotting studies. We conclude from these findings that these KCa channels are regulated through tyrosine phosphorylation/dephosphorylation; JAK2 tyrosine kinase, constitutively associated with PRL-R, is implicated in PRL stimulation of KCa channels.
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PMID:Role of tyrosine phosphorylation in potassium channel activation. Functional association with prolactin receptor and JAK2 tyrosine kinase. 759 39

The receptor for interleukin-5 (IL-5R) is composed of a unique alpha chain (IL-5R alpha) expressed on eosinophils and basophils, associated with a beta c subunit, which is shared by the receptors for IL-3 and granulocyte macrophage-colony stimulating factor. One of the molecular events activated via the IL-5R is the JAK/STAT signaling pathway. Recent reports have shown that IL-5 induces tyrosine phosphorylation of JAK2 followed by the subsequent cell type-specific activation of either STAT1 alpha or STAT5. To identify additional STAT proteins activated by IL-5, we co-transfected the IL-5R with STAT cDNAs in COS cells. We found that IL-5 induces binding of STAT3 to the intercellular adhesion molecule-1 pIRE, and activates STAT3-dependent transcription. Moreover, endogenous STAT3 was tyrosine phosphorylated and activated in human IL-5-stimulated BaF3 cells ectopically expressing the human IL-5R (BaF3/IL5R). These data imply that multiple STAT proteins are involved in gene regulation by IL-5 in a cell type-specific manner. We further demonstrate using C-terminal truncations of the alpha and beta c subunits of the IL-5R that the membrane-proximal STAT activation. Interestingly, a beta c receptor mutant lacking intracellular tyrosine residues is able to mediate STAT3 activation, suggesting that tyrosine phosphorylation of the beta c receptor is not essential for STAT3 activation.
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PMID:Activation of the STAT3/acute phase response factor transcription factor by interleukin-5. 759 60

Members of the Janus family (JAK) of protein tyrosine kinases are critical enzymes in signaling pathways via hematopoietin receptors. We have cloned JAK3, which unlike other known family members (JAK1, JAK2, and TYK2) is preferentially expressed in hematopoietic cells but not in a variety of other cells. Functionally, JAK3 and JAK1 are coupled to the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 in T cells and NK cells. Because of the importance of IL-2, IL-4, and IL-7 in B cell physiology, we sought to determine whether JAK3 was also present in B lymphocytes and whether it was involved in signaling via cytokines that are important for B cell development and function. In this report, we demonstrate that JAK3 is expressed in normal human peripheral blood B cells at levels that are comparable to those in T cells. In addition, the levels were found to be markedly up-regulated following stimulation with staphylococcal protein A Cowan and anti-CD40 Abs. In addition, IL-4 and IL-7 induced the rapid tyrosine phosphorylation of JAK3 and JAK1, and IL-4 activated both JAK3 and JAK1 phosphotransferase activity. JAK3 protein was also detected in immature B cell lines, but not in more well differentiated cell lines. Additionally, JAK3 was detected in lysates from bone marrow lymphoblasts of patients with B cell precursor acute lymphocytic leukemia and cell lines derived from human B cell lymphomas. Together, these data suggest that the regulation of JAK3 expression and activity is likely to be important in B cell development and function.
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PMID:Regulation of JAK3 expression and activation in human B cells and B cell malignancies. 759 33

A complete cDNA clone encoding the rat JAK2 protein tyrosine kinase was isolated from an Nb2-SP (rat pre-T lymphoma cell line) cDNA library. The nucleotide (nt) and deduced amino acid (aa) sequences for this clone were determined and an open reading frame of 3399 bp, encoding a protein of a deduced mass of 130 kDa, was found. The coding regions of the rat and murine Jak2 clones share 93.4% nt identity and 97.1% aa identity. Northern analysis demonstrated that the 5-kb mRNA is highly abundant in brain and spleen, less abundant in skeletal muscle and testis, and detectable in kidney, heart, lung and liver. Translation of the rat Jak2 mRNA in rabbit reticulocytes results in a protein which is specifically immunoprecipitated by antibodies (Ab) recognizing JAK2, but not by Ab recognizing JAK1.
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PMID:Cloning of the gene encoding rat JAK2, a protein tyrosine kinase. 760 55

Genes encoding two members of the JAK family of protein tyrosine kinases, Jak-1 and Jak-2, have been mapped to mouse Chromosomes (Chrs) 4 and 19 respectively. These placements are consistent with the previously described location of human JAK1 and JAK2, which lie in regions of synteny on human Chrs 1p31-3 (JAK1) and 9p24 (JAK2). The location of Jak-2 in the mouse genome extends the region of homology between mouse Chr 19 and human Chr 9.
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PMID:Localization of genes for two members of the JAK family of protein tyrosine kinases to murine chromosomes 4 and 19. 761 27

The activation of src-related tyrosine kinases following IL-3 stimulation was examined in 32Dcl3 cells. Three src-related tyrosine kinases were activated following IL-3 stimulation: fyn, hck, and lyn. 32Dcl3 cells were transfected with retroviral vectors expressing each of these kinases and independent clones overexpressing each kinase were isolated. In cells overexpressing either fyn or hck, IL-3 stimulated a rapid increase in catalytic activity, which remained elevated longer compared with the kinetics observed in parental 32Dcl3 cells. An increase in the number of tyrosine-phosphorylated proteins in the presence and absence of IL-3 stimulation was observed in cells overexpressing fyn or hck. Transfection of 32Dcl3 cells with a retroviral vector encoding lyn also resulted in an elevated level of kinase activity, although the increase was not as dramatic as that observed with fyn or hck. Consistent with observations in parental 32Dcl3 cells, a high basal level of lyn kinase activity was observed in unstimulated lyn-transfected cells and IL-3 stimulation resulted in an approximate threefold increase in kinase activity. Overexpression of c-src in 32Dcl3 did not result in IL-3-stimulated activation of c-src, indicating specificity for fyn, hck, and lyn. While the overexpression of fyn, hck, or lyn in 32Dcl3 cells resulted in increased kinase activity and IL-3 stimulated tyrosine phosphorylation, it did not render the cells more sensitive to IL-3. These results suggests that in addition to the JAK2 tyrosine kinase, src-related kinases may play a significant role in signal transduction by cytokine receptors.
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PMID:Activation of src-related tyrosine kinases by IL-3. 763 26

Interleukin 12 (IL-12) is an important immunoregulatory cytokine whose receptor is a member of the hematopoietin receptor superfamily. We have recently demonstrated that stimulation of human T and natural killer cells with IL-12 induces tyrosine phosphorylation of the Janus family tyrosine kinase JAK2 and Tyk2, implicating these kinases in the immediate biochemical response to IL-12. Recently, transcription factors known as STATs (signal transducers and activators of transcription) have been shown to be tyrosine phosphorylated and activated in response to a number of cytokines that bind hematopoietin receptors and activate JAK kinases. In this report we demonstrate that IL-12 induces tyrosine phosphorylation of a recently identified STAT family member, STAT4, and show that STAT4 expression is regulated by T-cell activation. Furthermore, we show that IL-12 stimulates formation of a DNA-binding complex that recognizes a DNA sequence previously shown to bind STAT proteins and that this complex contains STAT4. These data, and the recent demonstration of JAK phosphorylation by IL-12, identify a rapid signal-transduction pathway likely to mediate IL-12-induced gene expression.
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PMID:Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. 763 86

Lactogenic hormones, PRL and placental lactogen, are important regulators of insulin secretion and islet beta-cell proliferation. In this study we examined the presence of PRL receptor immunoreactivity in pancreatic islets of Langerhans using PRL receptor monoclonal antibodies provided by Dr. Paul Kelly. Studies were performed using islets isolated from neonatal, adult, and day 14 pregnant rats. The islets were examined by immunohistochemistry and laser scanning confocal microscopy. In neonatal rat islets, PRL receptors were observed in beta- and alpha-cells, but not in delta-cells. Among islet beta- and alpha-cells there was heterogeneity of cellular staining for PRL receptors. A small portion of the cells was intensely stained for PRL receptors. However, the majority of the cells had a much lower level of staining intensity, suggesting that most islet cells have a low level of PRL receptors. In general, alpha-cells were more uniformly stained than beta-cells. Similar results were obtained with adult rat islets, in which, again, there was a large range of staining intensity and many cells with low levels of PRL receptor. Rats on day 14 of pregnancy had an increased level of islet PRL receptor expression compared with age-matched control animals. There was also a decrease in cellular heterogeneity for PRL receptors, with nearly all cells having a uniformly high level of PRL receptor expression. JAK2, the tyrosine kinase associated with PRL receptors, was examined in Nb2 cells and islets. JAK2 immunoreactivity was detected at the cell membrane in very low levels in Nb2 cells. It was also found in numerous vesicular structures in the cytoplasm, where it colocalized with PRL receptors. A prominent feature of all cells was the presence of JAK2 in the nucleus, but not the nucleolus. In islets, JAK2 immunoreactivity was similarly observed in the nucleus of nearly all cells. However, the vesicular cytoplasmic location of JAK2 was less frequently observed and did not colocalize with PRL receptors. For comparison, JAK2 immunoreactivity was examined in several other tissues where it was detected in fibroblasts (endomysial and endoneurial cells), smooth muscle cells, and ganglion cells in the pancreas. JAK2 was notably absent from pancreas acinar cells, hepatocytes, skeletal muscle cells, and Schwann cells. This study demonstrates the presence of PRL receptors in islet beta- and alpha-cells, but not delta-cells. There was an increase in PRL receptor expression in islets during pregnancy, which is commensurate with the up-regulation of islet function. In addition, JAK2 immunoreactivity was detected in most islet cells and Nb2 node cells.
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PMID:Prolactin receptors and JAK2 in islets of Langerhans: an immunohistochemical analysis. 764 17


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