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)

Erythropoietin (Epo) is believed to transduce a signal by bringing two Epo receptors into close proximity, enabling cross-phosphorylation. We compared monomeric Epos with homodimers in which two Epo monomers are linked by polyglycine. Monomeric Epo mutant R103A is unable to support Epo-dependent cell growth or trigger Janus kinase 2 and STAT5 activation, even at concentrations greater than 7,000 times that sufficient for wild-type Epo activity. In contrast, R103A homodimer induces proliferation and transduces signal at concentrations similar to that of wild-type Epo monomer and homodimer. These experiments show that two discrete domains on Epo are required for receptor binding and activation. Our results also suggest that the EpoR can be dimerized by different forms and sizes of molecules, as long as two recognition motifs are provided in the same molecule. Design of other dimeric molecules may enhance our understanding of cytokine specificity and signal transduction.
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PMID:Homodimerization restores biological activity to an inactive erythropoietin mutant. 955 5

One facet of cytokine receptor signaling involves the activation of signal transducers and activators of transcription (STATs). STATs are rapidly activated via tyrosine phosphorylation by Janus kinase (JAK) family members and subsequently inactivated within a short period. We investigated the effect of proteasome inhibition on interleukin-3 (IL-3) activation of the JAK/STAT pathway following stimulation of Ba/F3 cells. Treatment of Ba/F3 cells with the proteasome inhibitor, N-acetyl-L-leucinyl-L-leucinyl-norleucinal (LLnL), led to stable tyrosine phosphorylation of the IL-3 receptor, beta common (betac), and STAT5 following stimulation. The effects of LLnL were not restricted to the JAK/STAT pathway, as Shc and mitogen-activated protein kinase (MAPK) phosphorylation were also prolonged in LLnL-treated cells. Further investigation showed these stable phosphorylation events were the result of prolonged activation of JAK2 and JAK1. These observations were confirmed using pharmacologic inhibitors. In the presence of LLnL, stable phosphorylation of STAT5 and betac was abrogated if the tyrosine kinase inhibitor, staurosporine, was added. The effect of staurosporine on STAT5 phosphorylation could be overcome if the phosphatase inhibitor, vanadate, was also added, suggesting phosphorylated STAT5 could be stabilized by phosphatase, but not by proteasome inhibition per se. These observations are consistent with the hypothesis that proteasome-mediated protein degradation can modulate the activity of the JAK/STAT pathway by regulating the deactivation of JAK.
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PMID:Interleukin-3-induced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors. 955 73

Interaction between erythropoietin (EPO) and its membrane receptor induces the proliferation and differentiation of erythroid progenitors. Targeted disruption of the EPO receptor (EPOR) gene have clearly demonstrated the importance of the EPO/EPOR system for definitive erythroid cell survival and proliferation; however, in vitro rescue experiments have revealed that it is not essential for differentiation. The three-dimensional structure of the EPOR has been determined, and a biologically active 20 amino acid peptide has been shown to cause dimerization of the extracellular domain of EPOR. EPO activates the JAK2-STAT5 pathway, and two tyrosine residues (Y343, Y401) in the cytoplasmic domain of EPOR are important for STAT5 activation. However, the physiologic role of STAT5 in erythroid cell proliferation and differentiation is still controversial. Mutations that result in C-terminal deletion of EPOR are frequently found in familial erythrocytosis. Hematopoietic cell phosphatase, which binds to the C-terminal region, could be involved in negative regulation of EPOR function.
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PMID:Physiology and function of the erythropoietin receptor. 966 55

The STAT5 activation has important roles in cell differentiation, cell cycle control, and development. However, the potential implications of STAT5 in the control of apoptosis remain unexplored. To evaluate any possible link between the erythropoietin receptor (EpoR) JAK2/STAT5 transduction pathway and apoptosis, we have investigated apoptosis-resistant cells (ApoR) that arose from positive selection of the erythroid-committed Ba/F3EpoR cells triggered to apoptosis by ectopic expression of the HOX-B8 homeotic gene. We show that JAK2 is normally activated by Epo in both Ba/F3EpoR and ApoR cells. In contrast, both STAT5a and STAT5b isoforms are uniquely activated in a C-truncated form (86 kDa) only in ApoR cells. Analysis of ApoR and Ba/F3EpoR subclones confirmed that the switch to the truncated STAT5 isoform coincides with apoptosis survival and that ApoR do not derive from preexisting cells with a shortened STAT5. In addition, ApoR cells die in the absence of Epo. This indicates that resistance to apoptosis is not because of a general defect in the apoptotic pathway of ApoR cells. Furthermore, we show that the 86-kDa STAT5 protein presents a dominant-negative (DN) character. We hypothesize that the switch to a DN STAT5 may be part of a mechanism that allows ApoR cells to be selectively advantaged during apoptosis. In conclusion, we provide evidence for a functional correlation between a naturally occurring DN STAT5 and a biological response.
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PMID:Positive selection of apoptosis-resistant cells correlates with activation of dominant-negative STAT5. 969 22

Eosinophils, along with mast cells are key cells involved in the innate immune response against parasitic infection whereas the adaptive immune response is largely dependent on lymphocytes. In chronic parasitic disease and in chronic allergic disease, IL-5 is predominantly a T cell derived cytokine which is particularly important for the terminal differentiation, activation and survival of committed eosinophil precursors. The human IL-5 gene is located on chromosome 5 in a gene cluster that contains the evolutionary related IL-4 family of cytokine genes. The human IL-5 receptor complex is a heterodimer consisting of a unique alpha subunit (predominantly expressed on eosinophils) and a beta subunit which is shared between the receptors for IL-3 & GM-CSF (more widely expressed). The alpha subunit is required for ligand-specific binding whereas association with the beta subunit results in increased binding affinity. The alternative splicing of the alpha IL-5R gene which contains 14 exons can yield several alpha-IL-5R isoforms including a membrane-anchored isoform (alpha IL-5Rm) and a soluble isoform (alpha IL-5Rs). Cytokines such as IL-5 produce specific and non-specific cellular responses through specific cell membrane receptor mediated activation of intracellular signal transduction pathways which, to a large part, regulate gene expression. The major intracellular signal transduction mechanism is activation of non-receptor associated tyrosine kinases including JAK and MAP kinases which can then transduce signals via a novel family of transcriptional factors named signal transducers and activators of transcription (STATS). JAK2, STAT1, and STAT5 appear to be particularly important in IL-5 mediated eosinophil responses. Asthma is characterized by episodic airways obstruction, increased bronchial responsiveness, and airway inflammation. Several studies have shown an association between the number of activated T cells and eosinophils in the airways and abnormalities in FEV1, airway reactivity and clinical severity in asthma. It has now been well documented that IL-5 is highly expressed in the bronchial mucosa of atopic and intrinsic asthmatics and that the increased IL-5 mRNA present in airway tissues is predominantly T cell derived. Immunocytochemical staining of bronchial biopsy sections has confirmed that IL-5 mRNA transcripts are translated into protein in asthmatic subjects. Furthermore, the number of activated CD4 + T cells and IL-5 mRNA positive cells are increased in asthmatic airways following antigen challenge and studies that have examined IL-5 expression in asthmatic subjects before and after steroids have shown significantly decreased expression following oral corticosteroid treatment in steroid-sensitive asthma but not in steroid resistant and chronic severe steroid dependent asthma. The link between T cell derived IL-5 and eosinophil activation in asthmatic airways is further strengthened by the demonstration that there is an increased number of alpha IL-5R mRNA positive cells in the bronchial biopsies of atopic and non-atopic asthmatic subjects and that the eosinophil is the predominant site of this increased alpha IL-5R mRNA expression. We have also shown that the subset of activated eosinophils that expressed mRNA for membrane bound alpha IL-5r inversely correlated with FEV1, whereas the subset of activated eosinophils that expressed mRNA for soluble alpha IL-5r directly correlated with FEV1. Hence, not only does this data suggest that the presence of eosinophils expressing alpha IL-5R mRNA contribute towards the pathogenesis of bronchial asthma, but also that the eosinophil phenotype with respect to alpha IL-5R isoform expression is of central importance. Finally, there are several animal, and more recently in vitro lung explant, models of allergen induced eosinophilia, late airway responses (LARS), and bronchial hyperresponsiveness (BHR)--all of which support a link between IL-5 and airway eosinophilia and bronc
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PMID:IL-5 and IL-5 receptor in asthma. 969 19

Interleukin-5 (IL-5) stimulates proliferation and differentiation of B cells and eosinophils. IL-5 receptor (IL-5R) comprises alpha and (beta)c chains. IL-5 specifically binds to IL-5Ralpha and induces the recruitment of (beta)c to IL-5Ralpha. JAK2 and JAK1 tyrosine kinases are constitutively associated with hIL-5Ralpha and (beta)c, respectively and activated upon IL-5 stimulation. IL-5 induces tyrosine phosphorylations of cellular proteins including (beta)c and STAT5 and activates Btk. X-linked immunodeficient mice have B-cell-specific defects due to missense mutation of the btk gene. The cytoplasmic proline-rich regions of both IL-5Ralpha and (beta)c are essential for the IL-5 signalling. IL-5 appears to play a critical role in hypereosinophilic syndromes and atopic diseases. The treatment of animals with anti-IL-5 mAb can decrease the enhanced bronchial responsiveness induced by allergen sensitization. Clinical studies provide a strong impetus for investigating the means of modulating IL-5 effects.
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PMID:Interleukin 5 and B cell differentiation. 972 Jul 54

The mechanism by which early lymphoid cells are selectively transformed by v-Abl is currently unknown. Previous studies have shown constitutive activation of IL-4 and IL-7 signaling pathways, as measured by activation of Janus protein kinase (JAK)1, JAK3, STAT5, and STAT6, in pre-B cells transformed by v-Abl. To determine whether activation of these cytokine signaling pathways by v-Abl is important in the cellular events induced by the Abelson murine leukemia virus, the effects of IL-4 and IL-7 on pre-B cells transformed with a temperature-sensitive v-Abl mutant were examined. Whereas IL-4 had little or no effect, IL-7 delayed both the apoptosis and cell cycle arrest that occur upon v-Abl kinase inactivation. IL-7 also delayed the decreases in the levels of c-Myc, Bcl-2, and Bcl-xL that occur upon loss of v-Abl kinase activity. IL-7 did not maintain v-Abl-mediated differentiation arrest of the pre-B cells, as activation of NF-kappaB and RAG gene transcription was unaffected by IL-7. These results identify a potential role for IL-7 signaling pathways in transformation by v-Abl while demonstrating that a combination of IL-4 and IL-7 signaling cannot substitute for an active v-Abl kinase in transformed pre-B cells.
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PMID:IL-7 reconstitutes multiple aspects of v-Abl-mediated signaling. 979 89

Interleukin (IL)-4 signaling proceeds via cytoplasmic activation of the Janus kinases JAK1 and JAK3 and the signal transducer and activator of transcription STAT6. We show that the IL-4 receptor, like other cytokine receptor systems utilizing the common receptor gamma-chain (gammac), is also connected to a signaling pathway that involves STAT5. Both STAT5a and STAT5b become tyrosine-phosphorylated and acquire specific DNA-binding properties in response to IL-4 receptor stimulation in the murine pro-B cell line Ba/F3. In preactivated human T cells, STAT5 became activated in an IL-4-dependent fashion as assayed by IL-4-induced STAT5 translocation from the cytoplasm to the cell nucleus and by binding to cognate DNA. Moreover, stimulation of preactivated human T cells by IL-4 led to specific transcriptional up-regulation of STAT5 target genes. IL-4 receptor-mediated STAT5 activation is dependent on the presence of gammac and JAK3 within the receptor complex. In COS-7 cells, the JAK/STAT pathway leading from the IL-4 receptor to STAT5-dependent regulation of a reporter gene relied largely on coexpression of JAK3. In Ba/F3 cells, studies on signal transduction evoked by directed specific receptor homo- or heterodimerization revealed that STAT5 activation can be triggered exclusively by IL-4R heterodimers containing gammac.
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PMID:The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain. 981 29

Thrombopoietin (TPO), the primary physiological regulator of platelet production, was initially thought to be a lineage-specific factor acting predominantly on megakaryocytopoiesis. Detailed studies establish that this cytokine mediates biological effects on a broad spectrum of hematopoietic progenitor cells, including stem cells. TPO is a hormone constitutively produced mainly by the liver and kidney. Plasma TPO levels are regulated by the platelet and megakaryocyte mass through Mpl receptor binding, internalization and degradation. The Mpl receptor is a member of the hematopoietin receptor superfamily lacking intrinsic kinase activity. Upon ligand-induced Mpl homodimerization, the major signaling events for proliferation are mediated through the JAK2/STAT5 pathway, while differentiation might occur through a prolonged activation of the MAPK pathway. Preclinical and clinical studies demonstrate the potential use of TPO in a variety of contexts, but it is too early to evaluate its benefit in reducing platelet transfusion.
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PMID:Thrombopoietin and its receptor. 983 Nov 70

While IL-12 is known to activate JAK2 and TYK2 and induce the phosphorylation of STAT4 and STAT3, little is known regarding how the activation of these signaling molecules is related to the biologic effects of IL-12. Using an IL-12-responsive T cell clone (2D6), we investigated their requirements for proliferation and IFN-gamma production of 2D6 cells. 2D6 cells could be maintained with either IL-12 or IL-2. 2D6 lines maintained with IL-12 (2D6(IL-12)) or IL-2 (2D6(IL-2)) exhibited comparable levels of proliferation, but produced large or only small amounts of IFN-gamma, respectively, when restimulated with IL-12 after starvation of either cytokine. 2D6(IL-12) induced TYK2 and STAT4 phosphorylation. In contrast, their phosphorylation was marginally induced in 2D6(IL-2). The reduced STAT4 phosphorylation was due to a progressive decrease in the amount of STAT4 protein along with the passages in IL-2-containing medium. 2D6(IL-12) and 2D6(IL-2) similarly proliferating in response to IL-12 induced comparable levels of JAK2 activation and STAT5 phosphorylation. JAK2 was associated with STAT5, and IL-12-induced STAT5 phosphorylation was elicited in the absence of JAK3 activation. These results indicate that IL-12 has the capacity to induce/maintain STAT4 and STAT5 proteins, and that TYK2 and JAK2 activation correlate with STAT4 phosphorylation/IFN-gamma induction and STAT5 phosphorylation/cellular proliferation, respectively.
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PMID:Requirement for distinct Janus kinases and STAT proteins in T cell proliferation versus IFN-gamma production following IL-12 stimulation. 983 69


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