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)

Interleukin (IL)-13 and IL-4 are pleiotropic immunoregulatory cytokines that share many overlapping biological properties reflecting the fact that both can utilize a receptor complex composed of the IL-4 receptor-alpha (IL-4Ralpha) chain and the IL-13Ralpha chain. The cytoplasmic domain of the IL-13Ralpha is 60 amino acids long and is essential for IL-13-dependent growth. It contains a Pro-rich domain in the membrane-proximal region and two Tyr residues. Here we show that a truncated IL-13Ralpha, lacking the 38 carboxyl-terminal residues but retaining the Pro-rich region, can support IL-13-dependent proliferation, although with reduced efficiency. A Y402F mutant of the cytoplasmic domain of IL-13Ralpha supported normal IL-13-induced growth. However, tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), which we show is induced by IL-13 and IL-4 in cells that express the IL-13Ralpha, was significantly reduced. The cytoplasmic domain of IL-13Ralpha was constitutively associated with STAT3, Tyk2, and Janus kinase 1 (JAK1). IL-13-induced tyrosine phosphorylation of IL-13Ralpha in vivo could not be detected using anti-Tyr(P) antibodies. A glutathione S-transferase fusion protein of the cytoplasmic domain of IL-13Ralpha was phosphorylated on tyrosine in vitro by JAK1, JAK3, and Tyk2, although the tyrosine phosphorylation events mediated by Tyk2 and JAK3 were not detectable using anti-phosphotyrosine antibodies. These data, together with the demonstration that IL-13Ralpha associates constitutively with Tyk2 and that Tyr-402 is involved in IL-13-induced phosphorylation of STAT3, suggest that the latter is mediated by Tyk2. Tyrosine phosphorylation of STAT3, which was not necessary for IL-13-induced proliferation, may account for some of the effects of IL-4 and IL-13 on the function of their targets.
...
PMID:Characterization of the cytoplasmic domain of interleukin-13 receptor-alpha. 1040 22

The goal of this study was to investigate how bacterial LPS affects macrophage responsiveness to the activating factor IFN-gamma. Pretreatment of macrophages with LPS for <2 h increased the transcriptional response to IFN-gamma. In contrast, simultaneous stimulation with IFN-gamma and LPS, or pretreatment with LPS for >4 h, suppressed Stat1 tyrosine 701 phosphorylation, dimerization, and transcriptional activity in response to IFN-gamma. Consistently, the induction of MHCII protein by IFN-gamma was antagonized by LPS pretreatment. Neutralizing Abs to IL-10 were without effect on LPS-mediated suppression of Stat1 activation. Decreased IFN-gamma signal transduction after LPS treatment corresponded to a direct induction of suppressor of cytokine signaling3 (SOCS3) mRNA and protein. Under the same conditions socs1, socs2, and cis genes were not transcribed. In transfection assays, SOCS3 was found to suppress the transcriptional response of macrophages to IFN-gamma. A causal link of decreased IFN-gamma signaling to SOCS3 induction was also suggested by the LPS-dependent reduction of IFN-gamma-mediated Janus kinase 1 (JAK1) activation. Further consistent with inhibitory activity of SOCS3, LPS also inhibited the JAK2-dependent activation of Stat5 by GM-CSF. Our results thus link the deactivating effect of chronic LPS exposure on macrophages with its ability to induce SOCS3.
...
PMID:Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-gamma. 1045 4

Kaposi's sarcoma-associated herpes virus (KSHV) is associated with Kaposi's sarcoma, multicentric Castleman's disease, and body cavity-based lymphomas, settings in which human interleukin-6 (hIL-6) acts as a growth factor. The KSHV open reading frame K2 encodes for viral IL-6 (vIL-6), a protein with 25% amino acid identity to hIL-6, which can promote the growth of hIL-6-dependent cell lines. In the present study, we characterized biological sequelae and signaling cascades triggered by hIL-6 versus vIL-6 in the hIL-6-dependent MH60 and B9 cell lines. Both hIL-6 and vIL-6 induced significant increases (P < 0.01) in DNA synthesis in these cell lines in a dose-dependent fashion. Neutralizing anti-hIL-6 antibody (Ab) inhibited DNA synthesis triggered by hIL-6, without similarly affecting proliferation in response to vIL-6. On the other hand, antimouse IL-6 receptor (mIL-6R) Ab blocked response to vIL-6, but not that to hIL-6. Both hIL-6 and vIL-6 activated gp130, Janus kinase 1, signal transducers and activators of transcription-3, and mitogen-activated protein kinase in both MH60 and B9 cells. Proliferation of these cell lines in response to both hIL-6 and vIL-6 was blocked by PD98059, an inhibitor of MEK1 activation. These data suggest that MEK1 activation mediates the proliferative response to both cytokines. Finally, both hIL-6 and vIL-6 also maintained viability of serum-starved MH60 and B9 cells and blocked dexamethasone-induced apoptosis of MM.1S human myeloma cells. Further characterization of the signaling cascades mediating the growth and antiapoptotic effects of vIL-6 versus hIL-6 may help identify their unique roles in disease pathogenesis in Kaposi's sarcoma and other KSHV-associated neoplasms.
...
PMID:Characterization of signaling cascades triggered by human interleukin-6 versus Kaposi's sarcoma-associated herpes virus-encoded viral interleukin 6. 1074 50

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.
...
PMID:Involvement of JAK/STAT (Janus kinase/signal transducer and activator of transcription) in the thyrotropin signaling pathway. 1080 30

Suppressor of cytokine signaling (SOCS) family proteins were originally identified as cytokine-induced negative regulators of cytokine signaling. We show that SOCS-1 and SOCS-3 inhibit interleukin (IL)-4-dependent signal transducer and activator of transcription 6 (Stat6) activation of and subsequent gene induction. By contrast, SOCS-2 and cytokine-inducible Src homology domain 2 (SH2)-containing protein up-regulate these processes. IL-4 initiates transmembrane signaling through two types of receptor complexes comprising the IL-4Ralpha subunit and the associated Janus kinase 1 (Jak1) as common essential components. We demonstrate that both SOCS-1- and SOCS-3-mediated down-regulation of IL-4 signaling is due to an inhibition of the receptor associated Jak1 activity. The SOCS proteins contain an amino-terminal region of variable length and primary structure, a central SH2 domain, and a carboxyl-terminal conserved motif termed SOCS-box. We show that the SH2 domains of SOCS-2, SOCS-3, and cytokine-inducible SH2-containing protein are functionally redundant in regulating the IL-4-dependent Jak-Stat signaling. The Pre-SH2 domains of SOCS-2 and SOCS-3 confer the specificity of their regulatory function. Importantly, the Pre-SH2 domain of SOCS-3 alone can inhibit IL-4 signaling. The SH2-proximal 25 amino acids of SOCS-3 are sufficient for this inhibition, and the Thr residue at position 24 and the Phe residue at position 25 are individually indispensable for its inhibitory function. Thus, the Thr-Phe motif in the Pre-SH2 domain plays a critical role in SOCS-3-mediated inhibition of the IL-4-dependent Jak-Stat signaling, likely by regulating the mode of SOCS-Jak interaction.
...
PMID:Identification of critical residues required for suppressor of cytokine signaling-specific regulation of interleukin-4 signaling. 1095 Sep 67

Epithelial chloride (Cl-) transport is achieved by the coordinated action of symporters such as the Na+-K+-2Cl- cotransporter (NKCC1) and chloride channels such as the cystic fibrosis transmembrane conductance regulator (CFTR). As a secretory tissue, mammary epithelial cells are obvious candidates for such mechanisms, but Cl- transport and its hormonal regulation have been poorly delineated in mammary epithelial cells. We determined whether the mammary epithelial cell line, HC11, transports chloride and whether this was regulated by PRL, a hormone known to stimulate ion transport. HC11 cells express both CFTR and NKCC1. Exposure to PRL or PGE1 increased Cl- transport in HC11 cells. This was inhibited by the NKCC1 blocker, furosemide, and by the Cl- channel inhibitor, diphenylamine 2-carboxylate. Dose and time course of PRL action indicate that PRL had maximal effect on Cl- transport at 1 microg/ml and at 10 min of stimulation. Examination of the signaling pathways suggests that the PRL effect on Cl- transport does not involve an increase in [Ca2+]i or MAP kinase activity. RT-PCR analyses indicate that HC11 cells express mRNA for Janus kinase 1 (JAK1), JAK2, and signal transducer and activator of transcription 5 (STAT5) but not for JAK3. PRL treatment of HC11 cells increased phosphorylation of STAT5. The JAK2 inhibitor AG490 blocked phosphorylation of STAT5 and PRL-induced, but not PGE1-induced, Cl- transport. NKCC1, but not CFTR, is tyrosine phosphorylated in HC11 cells. PRL enhanced tyrosine phosphorylation of NKCC1, and this effect was attenuated by the JAK2 inhibitor AG490. These results are the first demonstrations of a role for tyrosine phosphorylation of NKCC1 and of the PRL-JAK2 cascade in the regulation of Cl- transport.
...
PMID:Janus kinase 2 (JAK2) regulates prolactin-mediated chloride transport in mouse mammary epithelial cells through tyrosine phosphorylation of Na+-K+-2Cl- cotransporter. 1111 34

We have previously shown that interferon-alpha (IFN alpha)-dependent tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is impaired by serine phosphorylation of IRS-1 due to the reduced ability of serine phosphorylated IRS-1 to serve as a substrate for Janus kinase 1 (JAK1). Here we report that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFN alpha signaling by serine phosphorylating IRS-1. We found that both FRAP and insulin-activated p70 S6 kinase (p70(s6k)) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1(511-772)). Importantly, only FRAP-dependent IRS-1(511-772) serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1. Furthermore, treatment of U266 cells with the FRAP inhibitor rapamycin increased IFN alpha-dependent tyrosine phosphorylation by twofold while reducing constitutive IRS-1 serine phosphorylation within S/T-P motifs by 80%. Taken together, these data indicate that FRAP, but not p70(s6k), is a likely physiologic IRS-1 serine kinase that negatively regulates JAK1-dependent IRS-1 tyrosine phosphorylation and suggests that FRAP may modulate IRS-dependent cytokine signaling.
...
PMID:Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. 1116 88

Germ-line mutations of the breast cancer susceptibility gene 1 (BRCA1) confer a high risk for breast and ovarian cancer in women and prostate cancer in men. The BRCA1 protein contributes to cell proliferation, cell cycle regulation, DNA repair and apoptosis; however, the mechanisms underlying these functions of BRCA1 remain largely unknown. Here, we showed that, in Du-145 human prostate cancer cells, enhanced expression of BRCA1 resulted in constitutive activation of signal transducer and activator transcription factor 3 (STAT3) tyrosine and serine phosphorylation. Moreover, Janus kinase 1 (JAK1) and JAK2, the upstream activators of STAT3, were also activated by BRCA1. Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2. Blocking STAT3 activation using antisense oligonucleotides significantly inhibited cell proliferation and triggered apoptosis in Du-145 cells with enhanced expression of BRCA1. These findings indicate that BRCA1 interacts with the components of the JAK-STAT signaling cascade and modulates its activation, which may provide a new critical survival signal for the growth of breast, ovarian and prostate cancers in the presence of normal BRCA1.
...
PMID:Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. 1116 68

Development of cytokine resistance is an important feature of melanoma cells during tumor progression. To study the mechanisms of interleukin-6 resistance, we examined an interleukin-6 sensitive (WM35) and an interleukin-6 unresponsive cell line (WM9). Interleukin-6 treatment resulted in rapid inhibition of cyclin-dependent kinase 2/cyclin E activity and accumulation of the hypophosphorylated retinoblastoma protein in WM35 but not in WM9 cells. In contrast to previous reports, no differences in the expression of the cyclin-dependent kinase 2 inhibitor p21Cip1/WAF1 upon interleukin-6 treatment were found in both cell lines. Interleukin-6-induced inhibition of cyclin-dependent kinase 2 was also not due to changes in protein expression of cyclin-dependent kinase 2, cyclin E, p27Kip1 and cdc25A, a phosphatase positively regulating cyclin-dependent kinase 2 activity. As it is established that interleukin-6 resistance of WM9 cells is not caused by differential interleukin-6 receptor expression, we studied whether this is due to defective interleukin-6 signaling in which activation of signal transducer and activator of transcription 3 is a critical step. WM9 cells showed reduced tyrosine phosphorylation, DNA binding, and delayed nuclear translocation of signal transducer and activator of transcription 3 as compared with WM35 cells. The kinase upstream of signal transducer and activator of transcription 3, Janus kinase 1, was constitutively tyrosine-phosphorylated in WM9 cells and did not respond to interleukin-6 with increased phosphorylation. As compared with WM35 cells, interleukin-6 treatment of WM9 cells was not paralleled by reduced activity of the mitogen-activated protein kinase kinase-1, which suppresses activation of signal transducer and activator of transcription 3. Our data suggest that resistance of advanced melanoma cells to interleukin-6 is associated with reduced inhibition of cyclin-dependent kinase 2, which appears to be a consequence of a complex alteration in interleukin-6 signal transduction.
...
PMID:Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack of inhibition of cyclin E-associated kinase activity. 1144 60

Janus kinase 1 (Jak1) is a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors. Here we show that the in vitro translated N-terminal domains of Jak1 are sufficient for binding to a biotinylated peptide comprising the membrane-proximal 73 amino acids of gp130, the signal-transducing receptor chain of interleukin-6-type cytokines. By the fold recognition approach amino acid residues 36-112 of Jak1 were predicted to adopt a beta-grasp fold, and a structural model was built using ubiquitin as a template. Substitution of Tyr(107) to alanine, a residue conserved among Jaks and involved in hydrophobic core interactions of the proposed beta-grasp domain, abrogated binding of full-length Jak1 to gp130 in COS-7 transfectants. By further mutagenesis we identified the loop 4 region of the Jak1 beta-grasp domain as essential for gp130 association and gp130-mediated signal transduction. In Jak1-deficient U4C cells reconstituted with the loop 4 Jak1 mutants L80A/Y81A and Delta(Tyr(81)-Ser(84)), the interferon-gamma, interferon-alpha, and interleukin-6 responses were similarly impaired. Thus, loop 4 of the beta-grasp domain plays a role in the association of Jak1 with both class I and II cytokine receptors. Taken together the structural model and the mutagenesis data provide further insight into the interaction of Janus kinases with cytokine receptors.
...
PMID:Mapping of a region within the N terminus of Jak1 involved in cytokine receptor interaction. 1146 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---