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)

Ligand-induced receptor down-regulation by endocytosis is a critical process regulating the intensity and duration of receptor tyrosine kinase signaling. Ubiquitylation of specific receptor tyrosine kinases, for example, the epidermal growth factor receptor (EGFR) by the E3 ubiquitin ligase c-Cbl, provides a sorting signal for lysosomal degradation and leads to termination of receptor signaling. Cortactin, which couples the endocytic machinery to dynamic actin networks, is encoded by EMS1, a gene commonly amplified in breast and head and neck cancers. One mechanism whereby cortactin overexpression contributes to tumor progression is by enhancing tumor cell invasion and metastasis. However, in this study, we show that overexpression of cortactin in HeLa cells markedly inhibits ligand-induced down-regulation of the EGFR. This is independent of alterations in receptor autophosphorylation and correlates with impaired c-Cbl phosphorylation and association with the EGFR, reduced EGFR ubiquitylation, and sustained EGF-induced extracellular signal-regulated kinase activation. Furthermore, analysis of a panel of head and neck squamous cell carcinoma (HNSCC) cell lines revealed that cortactin overexpression is associated with attenuated ligand-induced EGFR down-regulation. Importantly, RNAi-mediated reduction of cortactin expression in an 11q13-amplified HNSCC cell line accelerates EGFR degradation. This represents the first demonstration of modulation of growth factor receptor signaling by cortactin. Moreover, enhanced EGFR signaling due to cortactin overexpression may provide an alternative explanation for EMS1 gene amplification in human cancers.
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PMID:Cortactin overexpression inhibits ligand-induced down-regulation of the epidermal growth factor receptor. 1583 60

Ubiquitin-protein ligase Cbl-b negatively regulates high affinity IgE receptor (FcepsilonRI)-mediated degranulation and cytokine gene transcription in mast cells. In this study, we have examined the role of a truncated variant of Cbl-b related to the rat model of type 1 diabetes mellitus using the mast cell signaling model. Overexpression of the truncated Cbl-b that lacks the C-terminal region did not suppress the activation of proximal and distal signaling molecules leading to degranulation. FcepsilonRI-mediated tyrosine phosphorylation of Syk, Gab2, and phospholipase C-gamma1, and activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAP kinase), and inhibitor of nuclear factor kappaB kinase (IKK), and generation of Rac1 are unaffected in cells overexpressing the truncated Cbl-b in the lipid raft. On the other hand, FcepsilonRI-mediated transcriptional activation of nuclear factor of activated T cells (NFAT), and transcription of interleukin-3 (IL-3) and IL-4 mRNA are inhibited by overexpression of the truncated variant of Cbl-b. This suppression parallels the re-compartmentalization of specific effector molecules in the lipid raft. These structural and functional analyses reveal the mechanism underlying the selective inhibition of cellular signaling by the truncated variant of Cbl-b related to insulin-dependent diabetes mellitus.
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PMID:Selective inhibition of Fcepsilon RI-mediated mast cell activation by a truncated variant of Cbl-b related to the rat model of type 1 diabetes mellitus. 1600 93

Alternative splicing of signaling proteins can contribute to the complexity of signaling networks. We find that expression of mouse RON, but not human RON, results in constitutive receptor autophosphorylation, ligand-independent activation of the mitogen-activated protein kinase pathway, and association of the receptor with c-Src. Using chimeric receptors, we mapped the region for this difference in signaling capacity of mouse and human RON to the juxtamembrane domain. Expression of these receptors in primary erythroid progenitor cells also demonstrated a functional difference in the ability of mouse and human RON to support erythropoietin-independent colony formation that mapped to the juxtamembrane domain. Splicing of the mouse RON receptor tyrosine kinase transcript results in the constitutive deletion of an exon used by all other known RON orthologs that encodes part of the juxtamembrane domain of the receptor. Mutational analysis indicated that the two tyrosines present in this region in human RON, one of which has been previously shown to be a c-Cbl binding site, are not responsible for this difference. However, deletion of this region in the context of human RON enhanced receptor phosphorylation, activation of mitogen-activated protein kinase, and association of c-Src at levels comparable with those observed with mouse RON. These data provide direct evidence that the divergence of exon usage among different species can generate a protein with novel activity and subsequently add to the complexity of cellular signaling regulation.
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PMID:Altered exon usage in the juxtamembrane domain of mouse and human RON regulates receptor activity and signaling specificity. 1616 96

The novel insulin receptor substrate protein APS is highly expressed in insulin-sensitive tissues and plays an important role in insulin-mediated glucose uptake and GLUT4 translocation via the Cbl/CAP pathway. Tyrosine phosphorylation of APS leads to recruitment of c-Cbl and Crk, while overexpression of APS mutant inhibits GLUT4 translocation in response to insulin, but the regulation of APS expression in skeletal muscle has not been previously reported. L6 myoblasts were differentiated in 2% FBS and serum starved for 24h prior to stimulation for 24h with either insulin 1 microM (n=6), rosiglitazone 10 microM (n=6), resistin 500 nM (n=6) or the MAP kinase inhibitor PD098059 50 microM (n=6) for 30 min, followed by insulin 1 microM for 24h. Semi-quantitative real-time RT-PCR was used to determine the expression of APS mRNA relative to the control gene TF2D. APS expression was markedly upregulated by myoblast differentiation (0.55+/-0.08 versus 1.14+/-0.08, p=0.001), and this effect was augmented by addition of rosiglitazone 10 microM for 24h to the differentiated myotubes (1.50+/-0.09, p=0.025). Insulin caused a 3.1-fold decrease in APS mRNA expression (0.37+/-0.01 versus 1.14+/-0.08, p=0.001), an effect that was attenuated by the MAP kinase inhibitor PD098059 (0.80+/-0.03, p=0.001). Exposure to resistin produced a modest decrease (1.4-fold) in myotube expression of APS (0.8+/-0.09, p=0.025). In conclusion, this is the first study to show that exposure to insulin markedly reduces the expression of APS in skeletal muscle via a MAP kinase dependent pathway, whereas myocyte differentiation and rosiglitazone increase APS expression. Changes in APS expression may be important in the aetiology and therapeutic reversal of insulin resistance in skeletal muscle.
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PMID:Contrasting effects of insulin and cellular differentiation on expression of the novel insulin receptor substrate APS in skeletal muscle. 1616 63

The Met receptor tyrosine kinase (RTK) regulates epithelial remodeling, dispersal, and invasion and is deregulated in many human cancers. It is now accepted that impaired down-regulation, as well as sustained activation, of RTKs could contribute to their deregulation. Down-regulation of the Met receptor involves ligand-induced internalization, ubiquitination by Cbl ubiquitin ligases, and lysosomal degradation. Here we report that a ubiquitination-deficient Met receptor mutant (Y1003F) is tumorigenic in vivo. The Met Y1003F mutant is internalized, and undergoes endosomal trafficking with kinetics similar to the wild-type Met receptor, yet is inefficiently targeted for degradation. This results in sustained activation of Met Y1003F and downstream signals involving the Ras-mitogen-activated protein kinase pathway, cell transformation, and tumorigenesis. Although Met Y1003F undergoes endosomal trafficking and localizes with the cargo-sorting protein Hrs, it is unable to induce phosphorylation of Hrs. Fusion of monoubiquitin to Met Y1003F is sufficient to decrease Met receptor stability and prevent sustained MEK1/2 activation. In addition, this rescues Hrs tyrosine phosphorylation and decreases transformation in a focus-forming assay. These results demonstrate that Cbl-dependent ubiquitination is dispensable for Met internalization but is critical to target the Met receptor to components of the lysosomal sorting machinery and to suppress its inherent transforming activity.
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PMID:Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs phosphorylation. 1622 11

Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation-driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer.
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PMID:Somatic mutations lead to an oncogenic deletion of met in lung cancer. 1639 41

Sprouty (Spry) proteins are negative feedback modulators of receptor tyrosine kinase pathways in Drosophila melanogaster and mammals. Mammalian Spry proteins have been shown to undergo tyrosine and serine phosphorylation in response to growth factor stimulation. While several studies have addressed the function of tyrosine phosphorylation of Spry, little is known about the significance of Spry serine phosphorylation. Here we identify mitogen-activated protein kinase-interacting kinase 1 (Mnk1) as the kinase that phosphorylates human Spry2 (hSpry2) on serines 112 and 121. Mutation of these serine residues to alanine or inhibition of Mnk1 activity increases the rate of ligand-induced degradation of hSpry2. Conversely, enhancement of serine phosphorylation achieved through either the inhibition of cellular phosphatases or the expression of active Mnk1 results in the stabilization of hSpry2. Previous studies have shown that growth factor stimulation induces the proteolytic degradation of hSpry2 by stimulating tyrosine phosphorylation on hSpry2, which in turn promotes c-Cbl binding and polyubiquitination. A mutant of hSpry2 that is deficient in serine phosphorylation displays enhanced tyrosine phosphorylation and c-Cbl binding, indicating that serine phosphorylation stabilizes hSpry2 by exerting an antagonistic effect on tyrosine phosphorylation. Moreover, loss of serine phosphorylation and the resulting enhanced degradation of hSpry2 impair its capacity to antagonize fibroblast growth factor-induced extracellular signal-regulated kinase activation. Our results imply that Mnk1-mediated serine phosphorylation of hSpry2 constitutes a regulatory mechanism to extend the temporal range of Spry activity.
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PMID:Regulation of sprouty stability by Mnk1-dependent phosphorylation. 1647 8

Stromal-cell-derived factor-1alpha (SDF-1alpha/CXCL12) is a potent chemoattractant for T cells. We report that Cbl family members, Cbl and Cbl-b, are tyrosine-phosphorylated after SDF-1alpha/CXCL12 stimulation of Jurkat T cells. Enhanced phosphorylation of Cbl and Cbl-b was regulated by src family kinases, and perhaps Fyn. Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma and Fyb after SDF-1alpha/CXCL12 stimulation, implicating association of these proteins in SDF-1alpha/CXCL12 actions. SDF-1alpha/CXCL12 did not induce tyrosine phosphorylation of Cbl or Cbl-b in Lck-deficient T cell line J.CaM1.6 or CD45-deficient T cell line J45.01. Thus, Lck Src kinase and tyrosine phosphatase CD45 are likely involved in regulating activation of Cbl family members. A functional role for Cbl and Cbl-b in migration was demonstrated by the decrease in SDF-1/CXCL12-induced migration in a T cell line in which transfected small interfering RNA for Cbl and Cbl-b decreased expression of Cbl and Cbl-b, but not MAPK activity. SDF-1alpha/CXCL12-induced chemotaxis was greatly reduced in the CD45-deficient T cell line. Our results implicate CD45, Cbl, Cbl-b, src kinases and potentially other associated proteins as mediators of SDF-1alpha/CXCL12-induced cell migration of Jurkat T cells.
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PMID:Stromal-cell-derived factor-1/CXCL12-induced chemotaxis of a T cell line involves intracellular signaling through Cbl and Cbl-b and their regulation by Src kinases and CD45. 1650 9

In this study we investigated the mechanisms mediating T-cell hyporesponsiveness in chronically immune-activated individuals. We analyzed in healthy and persistently helminth-infected individuals the relationship between immune activation and general T-cell hyporesponsiveness, Th3/regulatory T-cell expression, transforming growth factor-beta (TGF-beta) secretion, CTL-associated antigen 4 (CTLA-4) levels, Casitas B-cell lymphoma-b (Cbl-b) (a negative regulator of T-cell activation) levels and phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK)-1 and -2. We found a very significant increase in plasma levels of TGF-beta and intracellular pools of CTLA-4 and Cbl-b in association with immune activation, which correlates with decreased T-cell responses to anti-CD3 stimulation. We demonstrate that the impaired activity of ERK of peripheral T cells in highly immune-activated individuals is associated with increased levels of CTLA-4 and Cbl-b. Interestingly, in some, but not in all, of these immune-activated individuals, induction of Cbl-b intracellular pools occurs by TGF-beta or CTLA-4 stimulation. We suggest that the higher levels of CTLA-4 and TGF-beta, both involved in the induction of Cbl-b, point at potential mechanisms underlying general and antigen-specific immune hyporesponsiveness in chronically infected individuals.
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PMID:Increased TGF-beta, Cbl-b and CTLA-4 levels and immunosuppression in association with chronic immune activation. 1660 2

The development of macrophages from myeloid progenitor cells is primarily controlled by the growth factor colony stimulating factor-1 (CSF-1) and its cognate receptor, a transmembrane tyrosine kinase encoded by the c-Fms proto-oncogene. The CSF-1 receptor exerts its biological effects on cells via a range of signaling proteins including Erk1/2 and Akt. Here we have investigated the potential involvement of the Src-like adapter protein (SLAP-2) in signaling by the CSF-1 receptor in mouse bone marrow-derived macrophages. RT-PCR analysis revealed constitutive expression of the SLAP-2 gene in bone marrow macrophages. Surprisingly, co-immunoprecipitation and GST binding experiments demonstrated that the CSF-1 receptor could bind to SLAP-2 in a ligand-independent manner. Furthermore, the binding of SLAP-2 to the CSF-1 receptor involved multiple domains of SLAP-2. SLAP-2 also bound c-Cbl, with the interaction being mediated, at least in part, by the unique C-terminal domain of SLAP-2. Overexpression of SLAP-2 in bone marrow macrophages partially suppressed the CSF-1-induced tyrosine phosphorylation and/or expression level of a approximately 80 kDa protein without affecting CSF-1-induced global tyrosine phosphorylation, or activation of Akt or Erk1/2. Significantly, CSF-1 stimulation induced serine phosphorylation of SLAP-2. Pharmacologic inhibition of specific protein kinases revealed that CSF-1-induced phosphorylation of SLAP-2 was dependent on JNK activity. Taken together, our results suggest that SLAP-2 could potentially be involved in signaling by the CSF-1 receptor.
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PMID:A potential role for the Src-like adapter protein SLAP-2 in signaling by the colony stimulating factor-1 receptor. 1662 14


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