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)

We used a cultured murine cell model of the inner medullary collecting duct (mIMCD-3 cells) to examine the regulation of the ubiquitous sodium-proton exchanger, Na+/H+ exchanger isoform 1 (NHE-1), by a prototypical G protein-coupled receptor, the bradykinin B2 receptor. Bradykinin rapidly activates NHE-1 in a concentration-dependent manner as assessed by proton microphysiometry of quiescent cells and by 2'-7'-bis[2-carboxymethyl]-5(6)-carboxyfluorescein fluorescence measuring the accelerated rate of pH(i) recovery from an imposed acid load. The activation of NHE-1 is blocked by inhibitors of the bradykinin B2 receptor, phospholipase C, Ca2+/calmodulin (CaM), and Janus kinase 2 (Jak2), but not by pertussis toxin or by inhibitors of protein kinase C and phosphatidylinositol 3'-kinase. Immunoprecipitation studies showed that bradykinin stimulates the assembly of a signal transduction complex that includes CaM, Jak2, and NHE-1. CaM appears to be a direct substrate for phosphorylation by Jak2 as measured by an in vitro kinase assay. We propose that Jak2 is a new indirect regulator of NHE-1 activity, which modulates the activity of NHE-1 by increasing the tyrosine phosphorylation of CaM and most likely by increasing the binding of CaM to NHE-1.
...
PMID:Bradykinin B2 receptors activate Na+/H+ exchange in mIMCD-3 cells via Janus kinase 2 and Ca2+/calmodulin. 1127 60

The structure of human Janus kinase 2 (JAK2) comprising the two C-terminal domains (JH1 and JH2) was predicted by application of homology modelling techniques. JH1 and JH2 represent the tyrosine kinase and tyrosine kinase-like domains, respectively, and are crucial for function and regulation of the protein. A comparison between the structures of the two domains is made and structural differences are highlighted. Prediction of the relative orientation of JH1 and JH2 was aided by a newly developed method for the detection of correlated amino acid mutations. Analysis of the interactions between the two domains led to a model for the regulatory effect of JH2 on JH1. The predictions are consistent with available experimental data on JAK2 or related proteins and provide an explanation for inhibition of JH1 tyrosine kinase activity by the adjacent JH2 domain.
...
PMID:Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation. 1128 76

Stromal cell-derived factor-1 (SDF-1), the ligand for the CXCR4 receptor, is a highly efficacious chemoattractant for CD34(+) hematopoietic progenitor cells. However, the SDF-1/CXCR4 signaling pathways that regulate hematopoiesis are still not well defined. This study reports that SDF-1alpha can stimulate the tyrosine phosphorylation of Janus kinase 2 (JAK2) and other members of the JAK/signal transduction and activation of transcription (STAT) family, including JAK1, tyrosine kinase 2, STAT2, and STAT4 in the human progenitor cell line, CTS. SDF-1alpha stimulation of these cells also enhanced the association of JAK2 with phosphatidylinositol 3 (PI3)-kinase. This enhanced association was abolished by pretreatment of cells with AG490, a specific JAK2 inhibitor. Furthermore, pretreatment of CTS cells with AG490 significantly inhibited SDF-1alpha-induced PI3-kinase activity, and inhibition of JAK2 with AG490 ablated the SDF-1alpha-induced tyrosine phosphorylation of multiple focal adhesion proteins (including focal adhesion kinase, related adhesion focal tyrosine kinase, paxillin, CrkII, CrkL, and p130Cas). Chemotaxis assays showed that inhibition of JAK2 diminished SDF-1alpha-induced migration in both CTS cells and CD34(+) human bone marrow progenitor cells. Hence, these results suggest that JAK2 is required for CXCR4 receptor-mediated signaling that regulates cytoskeletal proteins and cell migration through PI3-kinase pathways in hematopoietic progenitor cells. (Blood. 2001;97:3342-3348)
...
PMID:Janus kinase 2 is involved in stromal cell-derived factor-1alpha-induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells. 1136 22

Erythropoietin (EPO) is the primary regulator of erythropoiesis, and promotes the survival, proliferation, and differentiation of erythroid progenitor cells. The EPO receptor belongs to the same family of receptors as growth hormone, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, and some interleukins. In the erythropoietic process, EPO induces homodimerization of the EPO receptor, which is located on the surface of erythroid progenitor cells. Dimerization activates the receptor-associated Janus kinase 2 via transphosphorylation. Specific tyrosines in the intracellular portion of the receptor are phosphorylated and serve as a docking site for intracellular proteins, including one of the signal transducers and activators of transcription (STAT5). This results in activating various cascades of signal transduction. STAT5 enters the nucleus on phosphorylation, inducing the transcription of erythroid genes. Phosphatases dephosphorylate Janus kinase 2 and downregulate the EPO receptor. Erythropoietin receptor activation seems to exert its effect by inhibiting apoptosis rather than by affecting the commitment of erythroid lineage, although the mechanism by which this occurs is as yet unclear. Anemia in cancer is associated with excessive production of cytokines that inhibit EPO synthesis, thereby interfering with the normal erythropoietic process, which leads to a reduction in red blood cells and the ability to oxygenate tissue.
...
PMID:The erythropoietin receptor. 1139 48

In this study, we report that the tyrosine kinase, Janus kinase 2 (Jak2), associates with the serine/threonine protein phosphatase 2A (PP2A) in 32Dcl3 myeloid progenitor cells. The association between Jak2 and PP2A transiently increases following interleukin-3 (IL-3) stimulation and activation of Jak2. The catalytic subunit of PP2A is tyrosine phosphorylated by Jak2 in vitro and in vivo, resulting in inhibition of phosphatase activity. PP2A also associates with Stat5 in 32Dcl3 cells in an IL-3-dependent manner. Pretreatment of 32Dcl3 cells with okadaic acid (OA), an inhibitor of PP2A, resulted in increased tyrosine phosphorylation and nuclear translocation of Stat5. Our results suggest that PP2A plays a negative regulatory role in regulating the IL-3 signaling pathway via formation of complexes with Jak2 and Stat5.
...
PMID:Involvement of protein phosphatase 2A in the interleukin-3-stimulated Jak2-Stat5 signaling pathway. 1144 Jun 34

Insulin and leptin have overlapping effects in the control of energy homeostasis, but the molecular basis of this synergism is unknown. Insulin signals through a receptor tyrosine kinase that phosphorylates and activates the docking proteins IRSs (insulin receptor substrates), whereas the leptin receptor and its associated protein tyrosine kinase JAK2 (Janus kinase 2) mediate phosphorylation and activation of the transcription factor STAT3 (signal transducer and activator of transcription). Here, we present evidence for the integration of leptin and insulin signals in the hypothalamus. Insulin induced JAK2 tyrosine phosphorylation, leptin receptor phosphorylation which, in the presence of leptin, augmented the interaction between STAT3 and this receptor. Insulin also increased the leptin-induced phosphorylation of STAT3 and its activation. These results indicate that insulin modulates the leptin signal transduction pathway, and may provide a molecular basis for the coordinated effects of insulin and leptin in feeding behavior and weight control.
...
PMID:Insulin modulates leptin-induced STAT3 activation in rat hypothalamus. 1144 68

In recent years, significant progress has been made in elucidating the signaling pathways activated by the growth hormone (GH) receptor. An initiating event is probably the activation of JAK2 (Janus kinase 2), a GH receptor-associated tyrosine kinase. Identification of the proteins recruited to the GH receptor-JAK2 complex and dissection of the signaling pathways that are subsequently activated will ultimately provide a basis for understanding GH action at the molecular level.
...
PMID:Signaling pathways activated by the growth hormone receptor. 1144 42

Monocyte chemotactic protein 1 (MCP-1), which is synthesized by vascular cells, is a chemoattractant for monocytes and has been implicated in a wide range of acute and chronic inflammatory processes characterized by monocyte infiltration, including atherosclerosis. However, it is unclear whether MCP-1 is able to modulate vascular smooth muscle cell (VSMC) proliferation. We assessed the effect of MCP-1 on VSMC proliferation and its interaction with serotonin (5-HT), a mitogen for VSMCs. Growth-arrested VSMCs were stimulated with different concentrations of MCP-1 (25-200 ng/ml) and 5-HT (5 and 50 microM) in serum-free medium. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. 5-HT at concentrations of 5 and 50 microM significantly stimulated DNA synthesis by 1.8- and 2.1-fold over the control value, respectively (p < 0.0001). However, MCP-1 at the concentrations tested did not have any significant effect on DNA synthesis. Even though MCP-1 (50 ng/ml) by itself is not mitogenic, when added to 5-HT, it significantly amplified the mitogenic effect of 5-HT compared with that of 5-HT alone (p < 0.0001). The 5-HT2A receptor antagonist sarpogrelate (10 microM) and its major metabolite M-1 (0.1 microM), pertussis toxin (10 ng/ml), Src family protein tyrosine kinase (PTK) inhibitor PP2 (1 microM), protein kinase C (PKC) inhibitor Ro31-8220 (0.1 microM) and mitogen-activated protein kinase (MAPK) kinase inhibitor PD098059 (10 microM) significantly inhibited the mitogenic effect of 5-HT and its interaction with MCP-1. Anti-MCP-1 antibody (2 microg/ml) and the Janus kinase 2 (JAK2) inhibitor AG490 (10 microM) significantly inhibited the interaction of MCP-1 with 5-HT. Further, the amplified mitogenic effect of 5-HT with MCP-1 was completely reversed by the combined use of sarpogrelate with anti-MCP-1 antibody. Our results suggest that MCP-1 amplifies the mitogenic effect of 5-HT on VSMCs. The mitogenic effect of 5-HT may be mediated by the G protein-Src family PTK-PKC-MAPK pathway. The activation of the JAK2/signal transducer and activator of transcription 3 pathway by MCP-1 in addition to the MAPK pathway by 5-HT may explain the potentiating effect of MCP-1 on 5-HT-induced mitogenesis.
...
PMID:Monocyte chemotactic protein 1 amplifies serotonin-induced vascular smooth muscle cell proliferation. 1145 5

Lps-defective C57BL/10ScCr (Cr) mice are homozygous for a deletion encompassing Toll-like receptor 4 that makes them refractory to the biological activity of LPS. In addition, these mice exhibit an inherited IL-12 unresponsiveness resulting in impaired IFN-gamma responses to different microorganisms. By positional cloning methods, we show here that this second defect of Cr mice is due to a mutation in a single gene located on mouse chromosome 6, in close proximity to the Igkappa locus. The gene is IL-12Rbeta2. Cr mice carry a point mutation creating a stop codon that is predicted to cause premature termination of the translated IL-12Rbeta2 after a lysine residue at position 777. The truncated beta2 chain can still form a heterodimeric IL-12R that allows phosphorylation of Janus kinase 2, but, unlike the wild-type IL-12R, can no longer mediate phosphorylation of STAT4. Because the phosphorylation of STAT4 is a prerequisite for the IL-12-mediated induction of IFN-gamma, its absence in Cr mice is responsible for their defective IFN-gamma response to microorganisms.
...
PMID:A point mutation in the IL-12R beta 2 gene underlies the IL-12 unresponsiveness of Lps-defective C57BL/10ScCr mice. 1148 94

Previous studies have indicated a redundancy in the effects of the cytokines, IL-3, IL-5, and nerve growth factor (NGF) on acute priming of human basophils. In the current study, we have examined the effects of these three cytokines on 18-h priming for leukotriene C4 generation, their ability to induce Fc(epsilon)RIbeta mRNA expression, or their ability to sustain basophil viability in culture. We also examine a variety of the signaling steps that accompany activation with these cytokines. In contrast with the ability of IL-3 to alter secretagogue-mediated cytosolic calcium responses following 18-h cultures, 18-h treatment with IL-5 or NGF did not affect C5a-induced leukotriene C4 generation or alter C5a-induced intracellular Ca2+ concentration elevations. IL-3 and IL-5, but not NGF, induced Fc(epsilon)RIbeta mRNA expression and all three improved basophil viability in culture with a ranking of IL-3 > IL-5 > or = NGF. All three cytokines acutely activated the extracellular signal-regulated kinase pathway and the signaling elements that preceded extracellular signal-regulated kinase and cytosolic phospholipase A2 phosphorylation, consistent with their redundant ability to acutely prime basophils. However, only IL-3 and IL-5 induced Janus kinase 2 and STAT5 phosphorylation. This pattern of signal element activation among the three cytokines most closely matched their ability to induce expression of Fc(epsilon)RIbeta mRNA. Induction of the sustained calcium signaling that follows overnight priming with IL-3 appeared to be related to the strength of the early signals activated by these cytokines but the relevant pathway required was not identified. None of the signaling patterns matched the ability of the cytokines to promote basophil survival.
...
PMID:Differences in functional consequences and signal transduction induced by IL-3, IL-5, and nerve growth factor in human basophils. 1149 16


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

---