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)

A monoclonal antibody (mAb; ACK2) recognizing the extracellular domains of the c-kit-encoded tyrosine kinase has been employed to demonstrate that c-kit is involved in B lymphocyte development. The c-kit-encoded tyrosine kinase is expressed on the surface of normal DHJH-rearranged murine pre-B cell clones which proliferate continuously at that stage in vitro on stromal cells and in the presence of recombinant interleukin 7. These pre-B cell clones, capable of differentiation to surface immunoglobulin-positive B cells in vitro and in vivo, are inhibited by the mAb in their proliferation while remaining capable of differentiation to surface immunoglobulin-positive B cells. Stimulation of mature B cells by mitogens is unimpaired by the mAb. This indicates that c-kit regulates early antigen-independent, but not late antigen-dependent, B cell development.
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PMID:The c-kit-encoded tyrosine kinase regulates the proliferation of early pre-B cells. 171 87

The signaling molecules insulin receptor substrate (IRS)-1 and the newly described IRS-2 (4PS) molecule are major insulin and interleukin 4 (IL-4)-dependent phosphoproteins. We report here that IL-2, IL-7, and IL-15, as well as IL-4, rapidly stimulate the tyrosine phosphorylation of IRS-1 and IRS-2 in human peripheral blood T cells, NK cells, and in lymphoid cell lines. In addition, we show that the Janus kinases, JAK1 and JAK3, associate with IRS-1 and IRS-2 in T cells. Coexpression studies demonstrate that these kinases can tyrosine-phosphorylate IRS-2, suggesting a possible mechanism by which cytokine receptors may induce the tyrosine phosphorylation of IRS-1 and IRS-2. We further demonstrate that the p85 subunit of phosphoinositol 3-kinase associates with IRS-1 in response to IL-2 and IL-4 in T cells. Therefore, these data indicate that IRS-1 and IRS-2 may have important roles in T lymphocyte activation not only in response to IL-4, but also in response to IL-2, IL-7, and IL-15.
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PMID:Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. 749 65

The thymic stromal network is complex and heterogeneous, containing thymic epithelial cells which are thought to play an important role during T-cell development and thymic fibroblasts which role is less defined. We herein present a phenotypic and functional comparison between defined thymic stromal cell populations. We transfected SV40 ori- into fetal and postnatal thymic stromal cell cultures and obtained SV40-immortalized clones of epithelial and fibroblastic nature as demonstrated by expression of intracellular keratin. These various clones were characterized in detail and compared to their untransfected bulk culture counterparts for phenotype, cytokine gene expression and cytokine production. All the different thymic stromal cells examined, constitutively expressed ICAM-1, LFA-3, MHC class I antigens, CD44, and the genes coding for IL-7, SCF and TGF-beta, but not TNF-alpha. After IL-1 stimulation, epithelial cells seemed to produce more GM-CSF than fibroblasts, and that trend was also seen for IL-6 secretion. SV40 cells were also regulated by IFN-gamma which induced MHC class II antigens and inhibited the IL-1 induced GM-CSF production. SV40 cells differed from their untransfected counterparts by an atypical expression of CD40 and lacked constitutive IL-1 alpha gene expression. We isolated clones with distinct properties, 24SV48, a highly proliferative CD34 positive TEC secreting low levels of GM-CSF and lacking constitutive IL-1 alpha and beta gene expression, and CT1SV93, an epithelial clone of postnatal origin with a high IL-1-induced cytokine production. In spite of differences with untransfected bulk cultures, the various SV40 immortalized clones may represent useful tools to further study the human thymic stroma.
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PMID:Untransfected and SV40-transfected fetal and postnatal human thymic stromal cells. Analysis of phenotype, cytokine gene expression and cytokine production. 750 57

Janus tyrosine kinase (JAK) has recently been linked to signal transduction by cytokine receptors of the hematopoietin family. We have recently described a 116-kDa tyrosine kinase (p116) present in interleukin-2 (IL-2) receptor complexes in human YT cells that showed functional characteristics of a JAK kinase. These included receptor association, rapid and transient tyrosine phosphorylation kinetics in response to ligand, and in vitro autophosphorylating tyrosine kinase activity (Kirken, R. A., Rui, H., Evans, G. A., and Farrar, W. L. (1993) J. Biol. Chem. 268, 22765-22770). Here we extend these observations by demonstrating structural homologies between IL-2-modulated p116 and prolactin-modulated JAK2 in the rat T cell line Nb2. These include similar net charge as determined by nonequilibrium pH gradient electrofocusing and related primary structure based upon phosphopeptide mapping of V8 protease-digested hyperphosphorylated proteins. This putative JAK kinase underwent marked tyrosine phosphorylation in response to IL-2, IL-4, and IL-7, lymphoid growth factors that use the common IL-2 receptor gamma-chain, but not in response to prolactin. Furthermore, polyclonal antisera to JAK1, JAK2, or tyrosine kinase 2 did not recognize either rat or human p116. However, we identified the IL-2-modulated p116 as the recently cloned novel leukocyte Janus kinase, L-JAK, using an antiserum to a peptide corresponding to the COOH terminus of human L-JAK.
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PMID:Identification of interleukin-2 receptor-associated tyrosine kinase p116 as novel leukocyte-specific Janus kinase. 751 51

The Janus family of kinases (JAKs) has been shown to be involved in the signal transduction of a number of cytokine receptors. Recently, we have cloned a novel JAK family member, JAK3, that is expressed in natural killer and activated T cells and is coupled functionally and physically to the interleukin 2 (IL-2) receptor in these cells. Here we report that JAK3 was expressed at low but detectable levels in human monocytes. In contrast, JAK3 expression was strongly induced during activation by interferon gamma (IFN-gamma) or lipopolysaccharide. Moreover, JAK3 became tyrosine phosphorylated in response to IL-2, IL-4, and IL-7 but not response to IFN-gamma or granulocyte/macrophage colony-stimulating factor. Together, these findings suggest that JAK3 is functionally important in activated monocytes and cells of the myeloid lineage and is involved in signaling responses of cytokines that use the common gamma-chain of the IL-2 receptor.
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PMID:Regulation of JAK3 expression in human monocytes: phosphorylation in response to interleukins 2, 4, and 7. 753 38

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 newly established human leukemia cell line, OM9;22, is reported, with B-precursor immunophenotype (CD10+ CD19+ CD22+ HLA- DR+ C mu-) and CD13 antigen, originated from a 19-year-old female patient with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL). The OM9;22 cells carry a Philadelphia (Ph) translocation and hybrid message detected by a minor-breakpoint cluster region (BCR) exon 1/ABL exon 2 junctional probe using reverse transcriptase polymerase chain reaction. The genetic alterations are consistent with those observed in the donor's leukemia cells, allowing us to conclude that this cell line is a minor-BCR rearranged Ph-positive ALL (Ph+ ALL). Colony formation of the OM9;22 cells in methylcellulose culture is enhanced by the addition of human interleukin 7 (IL-7). In liquid culture, more than 80% of IL-7-treated OM9;22 cells express CD20 antigen but fail to express surface immunoglobulins or cytoplasmic mu-chain, indicating that the cells have a potential of limited maturation by IL-7. By contrast, IL-4 suppresses the colony formation of the OM9;22 cells. These findings suggest that this cell line might be a model of B-precursor human leukemia with proliferative capability by IL-7.
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PMID:Interleukin-7 enhances colony growth and induces CD20 antigen of a Ph+ acute lymphoblastic leukemia cell line, OM9;22. 768 4

The gene regulatory functions of the human IL-2 receptor (IL-2R) were reconstituted in transiently transfected hepatoma cells. The combination of IL-2R beta and -gamma mediated a strong stimulation via the cytokine response element of the alpha 1-acid glycoprotein gene and the hematopoietin receptor response element, but none via the IL-6 response element or the sis-inducible element. IL-2R alpha enhanced 10-fold the sensitivity of the IL-2R beta.gamma complex to respond to IL-2 or IL-15, but did not modify the specificity or the magnitude of maximal gene regulation. A homodimerizing chimeric receptor G-CSFR-IL-2R beta could mimic the IL-2R action. The IL-2R-mediated gene regulation was similar to that seen with receptors for IL-4 and IL-7, but differed from that for IL-6 type cytokines, thrombopoietin, erythropoietin, and growth hormone. The activation of STAT proteins by the IL-2R was assessed in transfected L-cells and COS-1 cells. Although IL-2R subunits were highly expressed in these cells, no STAT protein activation was detectable. Transient overexpression of JAK3 was unable to change the signaling specificity of the hematopoietin receptors in rat hepatoma, L-, and COS cells, but established a prominent activation of the IL-6 response elements by the IL-2R and IL-4R in HepG2 cells. The data support the model that the IL-2R and related hematopoietin receptors produce at least two separate signals which control gene expression.
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PMID:The action of interleukin-2 receptor subunits defines a new type of signaling mechanism for hematopoietin receptors in hepatic cells and fibroblasts. 771 38

Interleukin (IL) 7 is an important cytokine regulating both T and B cell development and inducing the formation of lymphokine-activated killer cells and cytolytic T lymphocytes. This study reports the role of JAK family kinases in the IL-7 signalling pathway in a T cell clone. The results have shown that out of 4 members of JAK family tyrosine kinases (JAK1, JAK2, JAK3 and Tyk2), only JAK3 was tyrosine-phosphorylated and activated in cells of a T cell clone by stimulation with IL-7. Furthermore, STAT1 alpha (STAT, the signal transducers and activators of transcription) and p44 of MAPK (mitogen-activated protein kinases) were tyrosine phosphorylated by IL-7 stimulation, indicating that the two signal pathways might be involved in IL-7 signal transduction.
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PMID:JAK3 Janus kinase is involved in interleukin 7 signal pathway. 795 77

A member of the Src family of protein tyrosine kinases, Lyn is involved in the signaling pathways for cytokine or immunoglobulin-stimulated blood cells. Lyn is especially prominent in B-cell function. We have fine mapped LYN to chromosome 8q11-12 by fluorescence in situ hybridization. Of note, the gene for the pre-B cell growth factor, interleukin 7 (IL-7), has been mapped to 8q12-13. We show that IL-7 increases the protein tyrosine kinase activity of Lyn in the Daudi B-cell line. A third gene, HYRC, whose product may be involved in immunoglobulin rearrangement, has recently been localized to 8q11. We postulate that a lymphoid signaling region exists at 8q11-13.
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PMID:Localization of the human gene for Src-related protein tyrosine kinase LYN to chromosome 8q11-12: a lymphoid signaling cluster? 796 36


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