Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lyn-deficient mice were generated to analyze the role of Lyn in B cell antigen receptor (BCR) signaling. These mice had a reduced number of peripheral B cells with a greater proportion of immature cells and a higher than normal turnover rate. Aged lyn-/- mice developed splenomegaly, produced autoantibodies, and had an expanded population of B lymphoblasts of the B1 lineage. Splenic B cells from young lyn-/- mice initiated early BCR signaling events, although in a delayed fashion. Unexpectedly, lyn-/- B cells exhibited an enhanced MAP kinase activation and an increased proliferative response to BCR engagement. Stimulation of lyn-/- B cells with intact and F(ab')2 anti-IgM revealed defects in at least two mechanisms that negatively regulate BCR signaling, one of which involves Fc gammaRIIb1.
 ...
PMID:Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation. 925 21

TRAF2 is believed to mediate the activation of NF-kappaB and JNK induced by the tumor necrosis factor receptor (TNFR) superfamily, which elicits pleiotropic responses in lymphocytes. We have investigated the physiological roles of TRAF2 in these processes by expressing a lymphocyte-specific dominant negative form of TRAF2, thereby blocking this protein's effector function. We find that the TNFR superfamily signals require TRAF2 for activation of JNK but not NF-kappaB. In addition, we show that TRAF2 induces NF-kappaB-independent antiapoptotic pathways during TNF-induced apoptosis. Inhibition of TRAF2 leads to splenomegaly, lymphadenopathy, and an increased number of B cells. These findings indicate that TRAF2 is involved in the regulation of lymphocyte function and growth in vivo.
 ...
PMID:TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival. 939 Jun 93

The development of autoimmunity is correlated with heightened sensitivity of B cells to B cell Ag receptor (BCR) cross-linking. BCR signals are down-regulated by Lyn, which phosphorylates inhibitory receptors. lyn(-/-) mice have reduced BCR signaling thresholds and develop autoantibodies, glomerulonephritis, splenomegaly due to myeloid hyperplasia, and increased B-1 cell numbers. Bruton's tyrosine kinase (Btk), a critical component of BCR signaling pathways, is required for autoantibody production in lyn(-/-) mice. It is unclear whether Btk mediates autoimmunity at the level of BCR signal transduction or B cell development, given that lyn(-/-)Btk(-/-) mice have a severe reduction in conventional B and B-1 cell numbers. To address this issue, we crossed a transgene expressing a low dosage of Btk (Btk(low)) in B cells to lyn(-/-)Btk(-/-) mice. Conventional B cell populations were restored to levels similar to those in lyn(-/-) mice. These cells were as hypersensitive to BCR cross-linking as lyn(-/-) B cells as measured by proliferation, Ca(2+) flux, and activation of extracellular signal-regulated kinase and Akt. However, lyn(-/-)Btk(low) mice did not produce anti-ssDNA, anti-dsDNA, anti-histone, or anti-histone/DNA IgM or IgG. They also lacked B-1 cells and did not exhibit splenomegaly. Thus, B cell hyperresponsiveness is insufficient for autoimmunity in lyn(-/-) mice. These studies implicate B-1 and/or myeloid cells as key contributors to the lyn(-/-) autoimmune phenotype.
 ...
PMID:Reduced dosage of Bruton's tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in lyn-/- mice. 1290 86

Loss-of-function mutations in the murine dominant white spotting/c-kit locus affect a diverse array of biological processes and cell lineages and cause a range of phenotypes, including severe anemia, defective pigmentation, sterility, mast cell deficits, a lack of interstitial cells of Cajal, spatial learning memory deficits, and defects in peripheral nerve regeneration. Here we show that tyrosine residues 567 and 569 in the juxtamembrane (Jx) domain of the murine Kit receptor tyrosine kinase are crucial for the function of Kit in melanogenesis and mast cell development, but are dispensable for the normal development of erythroid, interstitial cells of Cajal and germ cells. Furthermore, adult mice lacking both tyrosines exhibit splenomegaly, dysregulation of B-cell and megakaryocyte development, and enlarged stomachs. Analysis of signal transduction events induced by the mutant receptors after ligand stimulation indicates that Jx tyrosine mutations diminish receptor autophosphorylation and selectively attenuate activation of extracellular signal-regulated kinase/mitogen-activated protein kinases. Together, these observations demonstrate that the Jx domain of Kit plays a cell-type specific regulatory role in vivo and illustrate how engineered mutations in Kit can be used to understand the complex biological and molecular events that result from activating a receptor tyrosine kinase.
 ...
PMID:Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages. 1506 26

TNF receptor (TNFR) superfamily members, CD40, and BAFFR play critical roles in B cell survival and differentiation. Genetic deficiency in a novel adaptor molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, and autoantibodies. While the B cell-specific Act1 knockout mice displayed a similar phenotype with less severity, the pathology of the Act1-deficient mice was mostly blocked in CD40-Act1 and BAFF-Act1 double knockout mice. CD40- and BAFF-mediated survival is significantly increased in Act1-deficent B cells, with stronger IkappaB phosphorylation, processing of NF-kappaB2 (p100/p52), and activation of JNK, ERK, and p38 pathways, indicating that Act1 negatively regulates CD40- and BAFF-mediated signaling events. These findings demonstrate that Act1 plays an important role in the homeostasis of B cells by attenuating CD40 and BAFFR signaling.
 ...
PMID:Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. 1548 34

During the initial phase of Friend virus (FV) induced erythroleukemia, the interaction between the viral envelope glycoprotein gp55, the Erythropoietin receptor (EpoR) and the naturally occurring truncated version of the Mst1r receptor tyrosine kinase, called Sf-Stk, drives the polyclonal expansion of infected progenitors in an erythropoietin independent manner. Sf-Stk provides signals that cooperate with EpoR signals to effect expansion of erythroid progenitors. The latter phase of disease is characterized by a clonal expansion of transformed leukemic cells causing an acute erythroleukemia in mice. Signaling by Sf-Stk and EpoR mediated by gp55 renders erythroid progenitors Epo independent through the activation of the EpoR downstream pathways such as PI3K, MAPK and JAK/STAT. Previous work has shown that Src family kinases also play an important role in erythropoiesis. In particular, mutation of Src and Lyn can affect erythropoiesis. In this report we analyze the role of the Lyn tyrosine kinase in the pathogenesis of Friend virus. We demonstrate that during FV infection of primary erythroblasts, Lyn is not required for expansion of viral targets. Lyn deficient bone marrow and spleen cells are able to form Epo independent FV colonies in vitro. In vivo infection of Lyn deficient animals also results in a massive splenomegaly characteristic of the virus. However, we observe differences in the pathogenesis of Friend erythroleukemia in Lyn-/- mice. Lyn-/- mice infected with the polycythemia inducing strain of FV, FVP, do not develop polycythemia suggesting that Lyn-/- infected erythroblasts have a defect in terminal differentiation. Furthermore, the expansion of transformed cells in the spleen is reduced in Lyn-/- mice. Our data show that Lyn signals are not required for susceptibility to Friend erythroleukemia, but Lyn plays a role in later events, the terminal differentiation of infected cells and the expansion of transformed cells.
 ...
PMID:Mutation of the Lyn tyrosine kinase delays the progression of Friend virus induced erythroleukemia without affecting susceptibility. 1652 51

An acquired JAK2 V617F mutation is found in most patients with polycythemia vera (PV), and about half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Mice transplanted with bone marrow cells in which JAK2 V617F was retrovirally expressed developed PV-like features, but not ET or PMF. To address the contribution of this mutation to the pathogenesis of these three MPDs, we generated two lines of JAK2 V617F transgenic mice. One line showed granulocytosis after 4 months of age. Among 43 mice, 8 (19%) showed polycythemia and 15 (35%) showed thrombocythemia. The second line showed extreme leukocytosis and thromobocytosis. They showed anemia that means Hb value from 9 to 10 g per 100 ml when 1 month old. Myeloid cells and megakaryocytes were predominant in the bone marrow of these animals, and splenomegaly was observed. The expression of JAK2 V617F mRNA in bone marrow cells was 0.45 and 1.35 that of endogenous wild-type JAK2 in the two lines, respectively. In vitro analysis of bone marrow cells from both lines showed constitutive activation of ERK1/2, STAT5 and AKT, and augmentation of their phosphorylations by cytokine stimulation. We conclude that in vivo expression of JAK2 V617F results in ET-, PMF- and PV-like disease.
 ...
PMID:Development of ET, primary myelofibrosis and PV in mice expressing JAK2 V617F. 1803 15

G1-4A, a polysaccharide from an Indian medicinal plant Tinospora cordifolia, was recently shown to protect mice against septic shock by modulating the proinflammatory cytokines. G1-4A also activated B cells polyclonally. The present report describes in detail the molecular events associated with G1-4A-induced immunomodulation in vitro and in vivo. G1-4A treatment led to an increase in the CD69 expression in lymphocytes. G1-4A-induced proliferation of B cells was completely inhibited by PI3K inhibitor Ly294002, mTOR inhibitor rapamycin and NF-kappaB inhibitor plumbagin. Akt, ERK and JNK were activated by G1-4A which finally resulted in the activation of IKK, degradation of IkappaB-alpha and translocation of NF-kappaB to the nucleus. Administration of G1-4A to mice led to splenomegaly and an increase in the numbers of T cells, B cells and macrophages. This increase in spleen cellularity was due to in vivo proliferation of lymphocytes and upregulation of anti-apoptotic genes. Anti-TLR4-MD2 complex antibody inhibited G1-4A-induced B cell proliferation and degradation of IkappaB-alpha suggesting that TLR-4 was a receptor for G1-4A on B cells. Activation of RAW 264.7 macrophages by G1-4A was found to be dependent on ERK and NF-kappaB-mediated signals. The phagocytosis index in peritoneal exudate cells (PEC) isolated from G1-4A treated mice was significantly higher as compared to that in PEC from control mice. G1-4A administration also increased the number of CD11b(+) cells in the PEC without an increase in the total number of PEC. Thus the present understanding of the molecular mechanism of action of G1-4A, a novel non-microbial TLR4 agonist, will pave the way for its application as an immunomodulator and adjuvant.
 ...
PMID:Molecular events in the activation of B cells and macrophages by a non-microbial TLR4 agonist, G1-4A from Tinospora cordifolia. 1942 53

IL-33, a member of the IL-1 family, activates MAPK and NF-kappaB through its receptor ST2L and IL-1RAcP. ST2, a member of the IL-1R superfamily, is a secreted form of ST2 gene products, which has been shown to act as a decoy receptor for IL-33 and to inhibit the IL-33/ST2L/IL-1RAcP signaling pathway. In this work, we generated ST2 transgenic mice. In control mice, intraperitoneal administration of IL-33 caused an increased number of eosinophils in blood and in peritoneal cavity, an increased number of peritoneal M Phi, splenomegaly, accumulation of periodic acid-Schiff-positive material in the lung, and high concentrations of serum IL-5 and IL-13. However, these alterations were hardly detectable in ST2 Tg mice. In peritoneal M Phi from IL-33-stimulated mice, mRNA expression of M2 M Phi marker genes were increased compared with thioglycollate-elicited peritoneal M Phi. The IL-33-stimulation also increased the secretion of IL-6 from M Phi. However, when the IL-33 was preincubated with ST2 prior to its addition to the M Phi cultures, the secretion of IL-6 was attenuated. These data suggest that, though IL-33 induced the Th2-type immune responses and infiltration of M2 type M Phi into the peritoneal cavity, ST2 can downregulate these reactions both in vivo and in vitro.
 ...
PMID:Characterization of ST2 transgenic mice with resistance to IL-33. 2066 97

Somatic gain-of-function mutations in members of the RAS subfamily of small guanosine triphosphatases are found in > 30% of all human cancers. We recently described a syndrome of chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity associated with a mutation in NRAS affecting hematopoietic cells, and initially we classified the disease as a variant of the autoimmune lymphoproliferative syndrome. Here, we demonstrate that somatic mutations in the related KRAS gene can also be associated with a nonmalignant syndrome of autoimmunity and breakdown of leukocyte homeostasis. The activating KRAS mutation impaired cytokine withdrawal-induced T-cell apoptosis through the suppression of the proapoptotic protein BCL-2 interacting mediator of cell death and facilitated proliferation through p27(kip1) down-regulation. These defects could be corrected in vitro by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 or phosphatidyl inositol-3 kinase inhibition. We suggest the use of the term RAS-associated autoimmune leukoproliferative disease to differentiate this disorder from autoimmune lymphoproliferative syndrome.
 ...
PMID:Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. 2139 97


1 2 3 4 Next >>