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)

The lymphocyte growth factors interleukin-2 (IL2), IL4, IL7, IL9 and IL15 use the common IL2 receptor-gamma (IL2R gamma) and activate the IL2R gamma-associated tyrosine kinase JAK3 (Janus kinase 3). IL13 is structurally related to IL4, competes with IL4 for binding to cell surface receptors and exhibits many similar biological effects. The molecular basis for this functional overlap between IL4 and IL13 has been attributed mainly to a shared use of the 140 kDa IL4R alpha, since these cytokines appear to be uniquely different in that, according to several recent reports, IL13 does not recruit the IL2R gamma or JAK3. This notion has been supported by the identification of a novel 70 kDa IL13 receptor in certain IL13-responsive cell lines that lack IL2R gamma. The present study sheds new light on the issue of functional overlap between IL13 and IL4, by demonstrating for the first time that, in cells that express both IL2R gamma and IL4R alpha, IL13 can mimic IL4-induced heterodimerization of IL2R gamma and IL4R alpha, with consequent marked activation of JAK3 and the transcription factor STAT6 (IL4-STAT). Reconstitution experiments in BA/F3 cells showed that both cytokines require the simultaneous presence of IL4R alpha and IL2R gamma to mediate JAK3 and proliferative responses, and analysis of 12 IL4R alpha variants showed that IL4 and IL13 signals were equally affected by mutations of the cytoplasmic domain. We conclude that IL13 activates the IL2R gamma-associated JAK3 tyrosine kinase in appropriate cell types, and propose that IL13 is capable of interacting with multiple receptor subunits in a cell-dependent and combinatorial manner. Consequently, we predict that partial disruption of IL13 signal transduction also contributes to the severe combined immuno-deficiency syndromes associated with inactivation of the IL2R gamma or JAK3 genes.
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PMID:Interleukin-13 is a potent activator of JAK3 and STAT6 in cells expressing interleukin-2 receptor-gamma and interleukin-4 receptor-alpha. 892 Sep 92

We cloned JAK3, the most recently described member of the JAK family of intracellular tyrosine kinases, from normal human CD34+ RNA. JAK3 is involved in the signal transduction pathways of the IL-2, IL-4, IL7, IL-9, and IL-15 receptors by association with their common gamma-chain (gamma[c]). JAK3 is critical to lymphoid development, as recently established by the linking of mutations in JAK3 to a subgroup of patients with SCID and the generation of JAK3-null mice with severe disruptions in normal lymphocytic development. However, JAK3 expression is not restricted to the lymphocytic compartment of bone marrow but is found in a wide range of tissues of both hematopoietic and non-hematopoietic origin. Northern blot analysis indicates that JAK3 is also expressed in adult placenta, lung, liver, kidney, pancreas, spleen, thymus, ovary, and small intestine. RNAse protection assays and RT-PCR indicate that JAK3 is expressed in a variety of leukemic-derived hematopoietic cell lines with myeloid and/or lymphoid phenotypes. In normal human bone marrow, JAK3 is expressed in the CD34+/lineage- fraction, which is highly enriched in hematopoietic stem/progenitor cells. In addition, we found a splice variant of JAK3 which is formed by the splicing of JAK3 with exon II of the leydig insulin-like (LEY I-L) hormone. RT-PCR and RNAse protection assay analyses indicate that this variant (termed I-JAK3) is normally expressed in almost all hematopoietic and non-hematopoietic tissues shown to express JAK3. Using fluorescence in situ hybridization we have localized JAK3 to 19p12-13.1, the same region of chromosome 19 to which the LEY I-L hormone maps (19p12-13.2).
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PMID:JAK3: expression and mapping to chromosome 19p12-13.1. 916 59

Cytokine pathways are essential for the differentiation and function of lymphoid cells. The major T-cell growth factor is IL-2, which is produced by subsets of T lymphocytes in response to antigenic stimulation. The IL-2 receptor is expressed by T cells after antigenic stimulation, and when engaged by IL-2 induces proliferation, differentiation, and protection from apoptosis. Rare patients with severe combined immune deficiency (SCID) have been found to have mature T lymphocytes that do not produce IL-2, although no genetic abnormality has yet been defined for these patients. The fact that these patients and IL-2 knockout mice have the ability to generate mature T lymphocytes indicates that IL-2 is the major growth factor for mature T lymphocytes but not for immature thymocytes. X-linked SCID, the most common form of SCID, has a phenotype of thymic hypoplasia, peripheral T lymphopenia, the presence of B lymphocytes that do not undergo normal class switching, and usually the absence of natural killer (NK) cells. X-SCID is caused by mutations of a receptor subunit, which was originally described as the IL-2Rgamma. The phenotypic differences between X-SCID and IL-2-deficient SCID suggests that the IL-2Rgamma chain might be a component of other receptors needed for thymic development, B cell class-switching, and NK development. The IL-2Rgamma is now known to be a shared subunit between the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, which explains the complex X-SCID phenotype. Because of this shared usage, the IL-2Rgamma is known as the common gamma chain (gamma c). Each ligand induces dimerization of gamma c with the ligand-specific receptor subunit, eg, the IL-2Rbeta, resulting in signal transduction through the JAK-STAT (signal transducers and activators of transcription) pathway. The JAK3 tyrosine kinase is constitutively associated with the gamma c and is necessary for signaling through the gamma c-containing receptors. Deficiency of JAK3 gives rise to a SCID phenotype that closely resembles that of X-SCID, but is autosomally recessive in inheritance. It is likely that other specific immune deficiencies of the cytokine pathways exist, eg, IL-7Ralpha-deficient SCID. T cells with wild-type gamma c and JAK3 proteins have a profound selective advantage over cells that contain mutant proteins. The selective advantage allows these patients to be treated by bone marrow transplantation (BMT) without ablative chemotherapy, and is the reason that these forms of SCID are potential targets for early gene therapy efforts.
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PMID:X-linked SCID and other defects of cytokine pathways. 980 Dec 59

Identification of cytokine-inducible genes is imperative for determining the mechanisms of cytokine action. A cytokine-inducible gene, mrg1 [melanocyte-specific gene (msg1) related gene], was identified through mRNA differential display of interleukin (IL) 9-stimulated and unstimulated mouse helper T cells. In addition to IL-9, mrg1 can be induced by other cytokines and biological stimuli, including IL-1alpha, -2, -4, -6, and -11, granulocyte/macrophage colony-stimulating factor, interferon gamma, platelet-derived growth factor, insulin, serum, and lipopolysaccharide in diverse cell types. The induction of mrg1 by these stimuli appears to be transient, with induction kinetics similar to other primary response genes, implicating its role in diverse biological processes. Deletion or point mutations of either the Box1 motif (binds Janus kinase 1) or the signal transducer and activator of transcription 3 binding site-containing region within the intracellular domain of the IL-9 receptor ligand binding subunit abolished or greatly reduced mrg1 induction by IL-9, suggesting that the Janus kinase/signal transducer and activator of transcription signaling pathway is required for mrg1 induction, at least in response to IL-9. Transfection of mrg1 cDNA into TS1, an IL-9-dependent mouse T cell line, converted these cells to IL-9-independent growth through a nonautocrine mechanism. Overexpression of mrg1 in Rat1 cells resulted in loss of cell contact inhibition, anchorage-independent growth in soft agar, and tumor formation in nude mice, demonstrating that mrg1 is a transforming gene. MRG1 is a transcriptional activator and may represent a founding member of an additional family of transcription factors.
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PMID:MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. 981 38

Severe combined immunodeficiency (SCID) is caused by multiple genetic defects. The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor gamma chain (gamma(c)) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal (T(-)B(+)NK(-)SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in Il7- or Il7r-deficient mice and that Il/7r-deficient mice have NK cells, we hypothesized that T(-)B(+)NK(+) SCID might result from defective IL-7 signalling, although apparent differences in the role of the IL-7/IL-7R pathway in humans and mice in T-cell and B-cell development have been suggested. We now demonstrate that defective IL7R expression causes T(-)B(+)NK(+) SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Ralpha signalling.
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PMID:Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. 984 16

The interleukin-2 (IL-2) receptor gamma chain (gammac) is shared by receptor complexes used by IL-2, IL-4, IL-7, IL-9 and IL-15, all of which are cytokines involved in lymphocyte development and/or activation. Gammac is physically and functionally associated with the JAK3 tyrosine kinase. This molecular pair may be considered as the trigger of the signalling cascades, inducing the activation of JAK1 upon heterodimerization with a cytokine-specific receptor component. JAK1, JAK3 and other tyrosine kinases, the nature of which varies between cytokines, phosphorylate the receptor, thereby creating docking sites for signalling molecules. Among them, PI 3-kinase and downstream effectors play a central role in the signalling processes involved in proliferation and inhibition of apoptosis for every gammac-interacting cytokine, although the mechanism of activation may vary between cytokines. Other important mediators--STAT transcription factors--regulate the expression of specific genes. IL-2, IL-7, IL-9 and IL-15 activate STAT3 and STAT5, in contrast to IL-4, which activates STAT6. These cytokines also trigger specific pathways, such as the MAP kinase cascade for IL-2 and IL-15, and the cascade responsible for immunoglobulin gene V-D-J rearrangement in response to IL-7.
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PMID:Signalling by cytokines interacting with the interleukin-2 receptor gamma chain. 1006 58

A novel Philadelphia (Ph) variant translocation, t(Y;9;22)(q12;q34;q11), was detected in a 63-year-old man with a newly diagnosed chronic myeloid leukemia (CML). Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed a b3a2 fusion transcript. Fluorescence in situ hybridization (FISH) utilizing library probes, subtelomeric cosmid probes, and probes hybridizing to the ABL and BCR genes showed a reciprocal three-way translocation involving Yq12, 9q34, and 22q11, and a BCR-ABL fusion signal on der(22). The subtelomeric Yq probe hybridizing centromerically to the IL9 receptor gene and covering the centromeric portion of the SYBL1 gene was found to be translocated to der(9).
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PMID:Novel Philadelphia variant t(Y;9;22)(q12;q34;q11) in a case of chronic myeloid leukemia. 1054 73

In a complementary DNA (cDNA) screening of murine Th2-skewed lymphocytes with our recently developed signal sequence trap method termed SST-REX, a novel type 1 cytokine receptor, Delta1 (delta1), was identified. Although delta1 is ubiquitously expressed in multiple tissues, the expression level is higher in Th2-skewed lymphocytes than in Th1-skewed ones. The delta1 cDNA encodes a 359-amino acid type 1 membrane protein. The extracellular domain of 206 amino acids showed 24% identity with the murine common gamma receptor that is shared among the receptors for interleukin(IL)-2, IL-4, IL-7, IL-9, and IL-15. The membrane-proximal region of delta1 includes a box1 motif, which is important for association with Janus kinases (JAKs), and showed a significant homology with that of the mouse erythropoietin receptor (EPOR). A box2 motif was also found in close proximity to the box1 region. Dimerization of the cytoplasmic region of delta1 alone did not transduce proliferative signals in IL-3-dependent cell lines. However, the membrane-proximal region of delta1 could substitute for that of human EPOR in transmitting proliferative signals and activating JAK2. These results suggest that delta1 is a subunit of cytokine receptor that may be involved in multiple receptor systems and play a regulatory role in the immune system and hematopoiesis.
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PMID:Molecular cloning of a novel type 1 cytokine receptor similar to the common gamma chain. 1073 86

A murine expressed sequence tag (EST) showing homology with erythropoietin receptor (EPOR) was identified in the EST database. Cloning of the full-length cDNA revealed a 359 amino acid novel type I cytokine receptor, designated cytokine receptor like molecule-2 (CRLM-2). While CRLM-2 lacks typical WSXWS motif, it has a significant homology with EPOR, IL-2 receptor beta and gamma, and IL-9 receptor alpha. The murine CRLM-2 gene is composed of 8 exons, and an alternative mRNA splicing generates a variant transcript encoding a soluble CRLM-2. CRLM-2 is preferentially expressed in hematopoietic cells, particularly in hematopoietic progenitors and myeloid cells. Furthermore, CRLM-2 is constitutively associated with JAK2, a well-known tyrosine kinase that transmits signals from cytokine receptors. These data strongly suggest that CRLM-2 is a novel cytokine receptor involved in the regulation of hematopoietic system.
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PMID:Molecular cloning and characterization of CRLM-2, a novel type I cytokine receptor preferentially expressed in hematopoietic cells. 1087 31

The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for IL-4, IL-7, IL-9, and IL-15 as well as IL-2. Here we show that the gamma(c) is also shared with the IL-21R complex. Although IL-21 binds to the IL-21R expressed on gamma(c)-deficient ED40515(-) cells, IL-21 is unable to transduce any intracytoplasmic signals. However, in EDgamma-16 cells, a gamma(c)-transfected ED40515(-) cell line, IL-21 binds to the IL-21R and can activate Janus kinase (JAK)1, JAK3, STAT1, and STAT3. The chemical cross-linking study reveals the direct binding of IL-21 to the gamma(c). These data clearly demonstrate that the gamma(c) is an indispensable subunit of the functional IL-21R complex.
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PMID:Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. 1141 23


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