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)

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

Human severe combined immunodeficiency (SCID) can be caused by defects in Janus kinase 3 (JAK3)-dependent cytokine signaling pathways. As a result, patients are at high risk of life-threatening infection. A JAK3 -/- SCID mouse model for the human disease has been used to test whether transplant with retrovirally transduced bone marrow (BM) cells (JAK3 BMT) could restore immunity to an influenza A virus. The immune responses also were compared directly with those for mice transplanted with wild-type BM (+/+ BMT). After infection, approximately 90% of the JAK3 BMT or +/+ BMT mice survived, whereas all of the JAK3 -/- mice died within 29 days. Normal levels of influenza-specific IgG were present in plasma from JAK3 BMT mice at 14 days after respiratory challenge, indicating restoration of B cell function. Influenza-specific CD4(+) and CD8(+) T cells were detected in the spleen and lymph nodes, and virus-specific CD8(+) effectors localized to the lungs of the JAK3 BMT mice. The kinetics of the specific host response correlated with complete clearance of the virus within 2 weeks of the initial exposure. By contrast, the JAK3 -/- mice did not show any evidence of viral immunity and were unable to control this viral pneumonia. Retroviral-mediated JAK3 gene transfer thus restores diverse aspects of cellular and humoral immunity and has obvious potential for human autologous BMT.
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PMID:Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency. 987 1

The SCID mouse represents a valuable tool for assessing growth characteristics and drug sensitivity of human leukemic cells. We have examined differences in the engraftment patterns in SCID mice of primary human leukemic cells isolated from children (< 21 years old) with either t(1;19)+/E2A-PBX1+ or t(9;22)+/BCR-ABL+ acute lymphoblastic leukemia. Leukemic cells from 13/24 t(1;19)+/E2A-PBX1+ patients caused overt leukemia in SCID mice. Macroscopic lesions were evident in 6/13 cases, with multiple sites involved in some mice: hepatomegaly,(3) splenomegaly(4), thymic enlargement; liver tumors(1), kidney tumors(1), abdominal tumors(1). Microscopic lesions in SCID mouse organs were present in all 13 cases and involved the bone marrow, brain, heart, gut, liver, kidney, lung, ovary, pancreas, skeletal muscle, spleen, and thymus. Leukemic cells from 5/20 t(9;22)+/BCR-ABL+ patients caused overt leukemia in SCID mice. Notably, macroscopic lesions (splenomegaly; leukemic bones; hepatic tumors) were observed in only 1 case. In all 5 cases, microscopic lesions were found in the mouse bone marrow. Additional microscopic lesions were restricted to skeletal muscle, spleen, and mesentery (1 case) or thymus (1 case). These findings differ markedly from those of t(1;19)+/E2A-PBX1+ leukemic cells due to the lack of involvement of major organs such as liver, pancreas, kidney, skin, or brain. These data illustrate the biological heterogeneity of childhood ALL and suggest that the differential risks associated with t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL ALL might arise from unique engraftment and proliferation capabilities of the respective leukemic cell populations.
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PMID:Distinct in vivo engraftment and growth patterns of t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL+ human leukemia cells in SCID mice. 1003 3

Retrovirus-mediated gene transfer into long-lived human pluripotent hematopoietic stem cells (HSCs) is a widely sought but elusive goal. A major problem is the quiescent nature of most HSCs, with the perceived requirement for ex vivo prestimulation in cytokines to induce stem cell cycling and allow stable gene integration. However, ex vivo culture may impair stem cell function, and could explain the disappointing clinical results in many current gene transfer trials. To address this possibility, we examined the ex vivo survival of nonobese diabetic/severe combined immune-deficient (NOD/SCID) repopulating cells (SRCs) over 3 days. After 1 day of culture, the SRC number and proliferation declined twofold, and was further reduced by day 3; self-renewal was only detectable in noncultured cells. To determine if the period of ex vivo culture could be shortened, we used a vesicular stomatitis virus G protein (VSV-G) pseudotyped retrovirus vector that was concentrated to high titer. The results showed that gene transfer rates were similar without or with 48 hours prestimulation. Thus, the use of high-titer VSV-G pseudotyped retrovirus may minimize the loss of HSCs during culture, because efficient gene transfer can be obtained without the need for extended ex vivo culture.
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PMID:One-day ex vivo culture allows effective gene transfer into human nonobese diabetic/severe combined immune-deficient repopulating cells using high-titer vesicular stomatitis virus G protein pseudotyped retrovirus. 1009 Sep 30

An in vivo lung tumor model system for radioimmunotherapy of lung metastases was used to test the relative effectiveness of the vascular- targeted beta-particle emitter 90Y, and alpha-particle emitter, 213Bi. Yttrium-90 was shown to be stably bound by CHXa" DTPA-MAb 201B conjugates and delivered efficiently to lung tumor blood vessels. Dosimetry calculations indicated that the lung received 16.2 Gy/MBq from treatment with 90Y MAb 201B, which was a sevenfold greater absorbed dose than any other organ examined. Therapy was optimal for 90Y with 3 MBq injected. Bismuth-213 MAb 201B also delivered a similar absorbed dose (15Gy/MBq) to the lung. Yttrium-90 was found to be slightly more effective against larger tumors than 213Bi, consistent with the larger range of 2 MeV beta particles from 90Y than the 8 MeV alpha particles from 213Bi. Treatment of EMT-6 tumors growing in immunodeficient SCID mice with 90Y or 213Bi MAb 201 resulted in significant destruction of tumor colonies; however, 90Y MAb 201B was toxic for the SCID mice, inflicting acute lung damage. In another tumor model, IC-12 rat tracheal carcinoma growing in SCID mouse lungs, 90Y therapy was more effective than 213Bi at destroying lung tumors. However, 90Y MAb 201B toxicity for the lung limited any therapeutic effect. We conclude that, although vascular-targeted 90Y MAb can be an effective therapeutic agent, particularly for larger tumors, in this model system, acute damage to the lung may limit its application.
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PMID:Treatment of lung tumor colonies with 90Y targeted to blood vessels: comparison with the alpha-particle emitter 213Bi. 1009 15

Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor-dependent myeloid precursor cells, STAT5 activation-deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation-deficient BCR/ABL SH3+SH2 mutants restored protection from apoptosis, stimulated growth factor-independent cell cycle progression, and rescued the leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor-independent proliferation, and the leukemogenic potential of these cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation-defective BCR/ABL SH3+SH2 mutants to induce growth factor-independent colony formation of primary mouse bone marrow progenitor cells. However, STAT5B-DAM did not rescue the growth factor-independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+ Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate that STAT5 activation by BCR/ABL is dependent on signaling from more than one domain and document the important role of STAT5-regulated pathways in BCR/ABL leukemogenesis.
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PMID:Signal transducer and activator of transcription (STAT)5 activation by BCR/ABL is dependent on intact Src homology (SH)3 and SH2 domains of BCR/ABL and is required for leukemogenesis. 1020 40

Janus kinases (JAK) play a crucial role in the initial steps of cytokine signaling. Each of the four members (JAK1, JAK2, JAK3, TYK2) of this non-receptor tyrosine kinase family is indispensable for the effects of distinct cytokines. Moreover, recent reports have added to our knowledge on their highly specific functions: JAK3 knockout mice and JAK3 deficient patients cannot signal through the interleukin-2,4,7,9, or 15 receptors and suffer from severe combined immunodeficiency (SCID). JAK1 and JAK2 knockout mice do not survive, their cells again showing distinct patterns of cytokine signaling deficits. At the other end of the spectrum, JAK fusion proteins have been shown to play a role in leukemias. In addition, a new class of JAK-specific inhibitors was described by several groups, the CIS/SOCS/Jab family. This review on the rapidly growing field focuses on JAK function and regulation, and on their emerging role in development and human disease.
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PMID:Janus kinases and their role in growth and disease. 1037 7

Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase required for T cell development and activated by cytokines that utilize the interleukin-2 (IL-2) receptor common gamma chain (gamma(c)). Genetic inactivation of JAK3 is manifested as severe combined immunodeficiency disease (SCID) in humans and mice. These findings have suggested that JAK3 represents a pharmacological target to control certain lymphoid-derived diseases. Here we provide novel evidence that AG-490 potently inhibits the autokinase activity of JAK3 and tyrosine phosphorylation and DNA binding of signal transducer and activator of transcription 5a and 5b (STAT5a/b). Similar inhibitory effects were observed with other cytokines that use gamma(c). AG-490 also inhibited IL-2-mediated proliferative growth in human T cells with an IC50) = 25 microM that was partially recoverable. Moreover, we demonstrate that this inhibitor prevented tetanus toxoid antigen-specific T cell proliferation and expansion but failed to block activation of Zap70 or p56Lck after anti-CD3 stimulation of human T cells. Taken together, these findings suggest that AG-490 inhibits the JAK3-mediated Type II signaling pathway but not the T cell receptor-derived Type I pathway and possesses therapeutic potential for T cell-derived pathologies such as graft-versus-host disease, allergy, and autoimmune disorders.
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PMID:Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells. 1038 Sep 15

The JAK3 gene, encoding a tyrosine kinase functionally coupled to cytokine receptors which share the common gamma chain, has been identified as the defective gene for autosomal recessive severe combined immunodeficiency (SCID). Thus, specific mutational diagnosis has become possible. We screened all exons with a combined single strand conformational polymorphism and hetero-duplex formation assay followed by sequence analysis to identify specific mutations in two families. This assay was used on chorionic villus sampling derived DNA in two fetuses from two unrelated families, where we found mutations in both parents. We were able to exclude the mutations in both fetuses by the 12th week of gestation. The described method for first-trimester prenatal diagnosis of autosomal recessive T-B+SCID provides a valid tool to aid in genetic counselling and possibly prenatal therapy in this disease.
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PMID:Prenatal diagnosis of JAK3 deficient SCID. 1041 14

In vitro maintenance and proliferation of human hematopoietic stem cells is crucial for many clinical applications. Early hematopoietic cells express low levels of FLT-3 and c-kit receptors, as well as the interleukin-6 (IL-6) receptor signal transducing element, gp130, but do not express IL-6 receptor itself. Therefore, we have attempted to maintain human cord blood or bone marrow CD34(+) cells ex vivo in serum-free cultures containing stem cell factor (SCF) and FLT-3 ligand (FL) alone or together with a new recombinant molecule of soluble IL-6 receptor fused to IL-6 (IL6RIL6 chimera). The effect of IL6RIL6 chimera on the proliferation and differentiation of CD34(+) cells was compared with that of each chimera component added separately. The engraftment potential of in vitro-cultured cells was determined using our recently established functional in vivo assay for primitive human severe combined immunodeficiency (SCID)-repopulating cells (SRC). We report here that IL6RIL6 chimera induced significantly higher levels of progenitors and SRC compared with SCF + FL alone or together with IL-6 and soluble IL-6 receptor. IL6RIL6 chimera prolonged in vitro maintenance of SRC for up to 14 days. Stimulation of CD34(+)CD38(-/low) enriched cells with IL6RIL6 chimera maintained the early CD34(+)CD38(-/low) cell subpopulation, which could be detected in vitro for up to 14 days. Moreover, IL6RIL6 chimera preferentially stimulated the growth of early CD34(+)38(-/low) cells, resulting in significantly higher levels of progenitors compared with more mature CD34(+)38(+) cells. Taken together, these findings demonstrate the importance of IL6RIL6 chimera in stimulating the proliferation of early CD34(+). CD38(-)gp130(+)IL-6R(-) cells in vitro and extended maintenance of progenitors and SRC.
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PMID:The soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro maintenance and proliferation of human CD34(+)CD38(-/low) cells capable of repopulating severe combined immunodeficiency mice. 1041 83


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