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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor receptor (EGFR) is a transmembrane protein that binds EGF in its extracellular domain and initiates signaling via intrinsic tyrosine kinase activity in its cytoplasmic domain. EGFR is important in development, cellular proliferation, and cancer. GH is a critical growthpromoting and metabolic regulatory hormone that binds the GH receptor, thereby engaging various signaling pathways, including ERKs. Prior studies suggest cross-talk between the GH receptor and EGFR signaling systems. Using the GH- and EGF-responsive 3T3-F442A preadipocyte, we previously observed that GH, in addition to causing EGFR tyrosine phosphorylation, also induced EGFR phosphorylation that was detected by PTP101, an antibody reactive with ERK consensus phosphorylation sites. This latter phosphorylation was prevented by pretreatment with MAPK kinase (MEK)1 inhibitors, suggesting ERK pathway dependence. Furthermore, GH cotreatment with EGF markedly slowed EGF-induced EGFR degradation and down-regulation, thereby potentiating EGF-induced EGFR signaling. These effects were also MEK1 dependent and suggested ERK pathway-dependent influence of GH on EGF-induced EGFR postendocytic trafficking and signaling. We now explore the impact of GH on cell surface binding of EGF in 3T3-F442A cells. We found that GH pretreatment caused transient, but substantial, lessening of (125)I-EGF binding. Competitive binding experiments revealed that the decreased binding was primarily due to decreased affinity, rather than a change in the number of EGF binding sites. The effect of GH on EGF binding was concentration dependent and temporally correlated with GH-induced ERK activation and EGFR PTP101-reactive phosphorylation. Blockade of the MEK1/ERK but not the protein kinase C pathway, prevented GH's effects on EGF binding, and our results indicate that the mechanisms of GH- and phorbol-12-myristate-13-acetateinduced inhibition of EGF binding differ substantially. Overall, our findings suggest that GH can modulate both EGF binding kinetics and the EGFR's postbinding signaling itinerary in a MEK1/ERK pathway-dependent fashion.
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PMID:Growth hormone alters epidermal growth factor receptor binding affinity via activation of extracellular signal-regulated kinases in 3T3-F442A cells. 1507 Aug 53

The fibroblast growth factors (FGFs) represent a large family of ligands that activate signal transduction pathways leading to diverse biological responses, including many involved in various processes during development. Here, we discuss the discovery of a subset of conserved FGF target genes that encode feedback regulators of FGF signaling itself. Members of the Sprouty, Sef, and mitogen-activated protein kinase phosphatase families are negative modulators of FGF signaling, whereas positive factors that promote FGF signaling include the ETS transcription factors ERM and PEA3 and the transmembrane protein XFLRT3. These molecules affect the FGF signaling cascade at different levels to regulate the final output of the pathway. This multilayered regulation suggests that precise adjustment of FGF signaling is critical in development.
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PMID:Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. 1508 62

SIRPbeta (signal-regulatory protein beta) is a transmembrane protein that is expressed in hematopoietic cells but whose functions are unknown. We have now cloned mouse SIRPbeta cDNA and have shown that the gene is expressed in various tissues in addition to cells of the macrophage lineage. Engagement of SIRPbeta by specific monoclonal antibodies promoted Fcgamma receptor-dependent or -independent phagocytosis in mouse peritoneal macrophages. It also induced marked activation of MAPK and the upstream kinase MEK but weak activation of Akt. MEK inhibitors markedly blocked the promotion of phagocytosis by SIRPbeta, whereas an inhibitor of phosphoinositide 3-kinase partly blocked such response. In addition, inhibitors of myosin light chain kinase or of myosin ATPase blocked the promotion of phagocytosis by SIRPbeta. Furthermore, SIRPbeta induced the formation of filopodia and lamellipodia in macrophages as well as the translocation of activated MAPK to these structures. It also elicited tyrosine phosphorylation of DAP12, Syk, and SLP-76, and a Syk inhibitor blocked the promotion of phagocytosis and activation of MAPK by SIRPbeta. Our results suggest that engagement of SIRPbeta promotes phagocytosis in macrophages by inducing the tyrosine phosphorylation of DAP12, Syk, and SLP-76 and the subsequent activation of a MEK-MAPK-myosin light chain kinase cascade.
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PMID:Positive regulation of phagocytosis by SIRPbeta and its signaling mechanism in macrophages. 1512 31

CD72 is a 45 kDa B cell-specific type II transmembrane protein of the C-type lectin superfamily. It was originally defined as a receptor-like molecule that regulates B cell activation and differentiation; however, its precise function remains unclear since more recent functional analyses, including a gene targeting study, suggest that CD72 may serve as a negative or a positive regulator of B cell signaling. In the present study, we analyzed the cell-autonomous function of CD72 in B cell receptor (BCR) signaling using CD72-deficient cells generated from mature BAL-17 cells. We found that BCR-mediated phosphorylation of CD19, Btk, Vav and phospholipase Cgamma2 and association of CD19 with phosphatidylinositol-3 kinase were impaired in CD72-deficient cells. Inositol trisphosphate synthesis was normally induced initially but ablated at 1 min of stimulation in CD72-deficient cells. In the event, Ca(2+) release from intracellular stores remained intact, though influx of extracellular Ca(2+) was severely impaired in CD72-deficient cells. Furthermore, BCR-evoked activation of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase, and growth inhibition in BAL-17 cells were blocked in the absence of CD72. Significantly, these effects were largely reversed by re-expression of CD72. Thus, CD72 appears to exert a positive effect on BCR signaling pathways leading to Ca(2+) influx and MAPK activation, which in turn may determine the fate of BAL-17 cells.
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PMID:Impairment of B cell receptor-mediated Ca2+ influx, activation of mitogen-activated protein kinases and growth inhibition in CD72-deficient BAL-17 cells. 1514 89

A major question in cell biology is how molecular specificity is achieved by different growth factor receptors that activate apparently identical signaling events. For the neurotrophin family, a distinguishing feature is the ability to maintain a prolonged duration of signal transduction. However, the mechanisms by which neurotrophin receptors assemble such a sustained signaling complex are not understood. Here we report that an unusual ankyrin-rich transmembrane protein (ARMS+kidins220) is closely associated with Trk receptor tyrosine kinases, and not the EGF receptor. This association requires interactions between transmembrane domains of Trk and ARMS. ARMS is rapidly tyrosine phosphorylated after binding of neurotrophins to Trk receptors and provides a docking site for the CrkL-C3G complex, resulting in Rap1-dependent sustained ERK activation. Accordingly, disruption of Trk-ARMS or the ARMS-CrkL interaction with dominant-negative ARMS mutants, or treatment with small interference RNA against ARMS substantially reduce neurotrophin-elicited signaling to ERK, but without any effect upon Ras or Akt activation. These findings suggest that ARMS acts as a major and neuronal-specific platform for prolonged MAP kinase signaling by neurotrophins.
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PMID:A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein. 1516 95

A seven-transmembrane protein, frizzled, has been implicated in a planar cell polarity (PCP) pathway as well as the canonical Wnt signaling pathway. Although both pathways require a cytoplasmic protein, dishevelled, the molecular mechanism by which frizzled regulates intracellular signaling remains to be elucidated. In the mouse, nine frizzled family members have been identified and six of them contain a PDZ-binding motif at their carboxyl-termini. In this study, we show that a multi-PDZ containing protein, MAGI-3, specifically binds to frizzled-4 and -7. Furthermore, we also demonstrate that MAGI-3 interacts with Ltap, a mouse homolog of the Drosophila PCP protein, stbm, and that these three molecules can form a ternary complex. In epithelial cells, MAGI-3, frizzled-4, and Ltap colocalized at cell contact sites, indicating that these molecules form a physiologically significant complex. Finally, we found that MAGI-3 strongly activated JNK in conjunction with frizzled-4 and Ltap, and that this activation required the small GTPase, Rac. These results indicate that MAGI-3 functions as a scaffold protein for frizzled-4 and Ltap and regulates the JNK signaling cascade.
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PMID:MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap. 1519 40

Early spherical Xenopus laevis embryos are transformed into a streamlined shape through convergent extension movements. Here we report that a p75(NTR)-related transmembrane protein, NRH1, has an essential function in the regulation of these movements. NRH1 was expressed in marginal zone tissues of the gastrula and in the posterior ectoderm of the neurula. Attenuation of the NRH1 function inhibited convergent extension movements in the embryo and in activin-treated animal caps. NRH1 activated downstream effectors of the Wnt/planar cell polarity pathway: small GTPases and the cascade of MKK7-JNK. Furthermore, gain- and loss-of-function phenotypes of NRH1 were rescued by co-injection of dominant-negative and constitutively active forms of these downstream effectors, respectively, suggesting that NRH1 functions as a positive modulator of planar cell polarity signalling. Interestingly, NRH1 does not require Dishevelled (Xdsh) for the activation of these downstream effectors or translocation of Xdsh to the membrane, suggesting that NRH1 signalling interacts with planar cell polarity signalling downstream of Xdsh. This demonstrates an essential role for p75(NTR)-related signalling in early embryonic morphogenesis.
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PMID:The neurotrophin-receptor-related protein NRH1 is essential for convergent extension movements. 1530 94

Integrins are heterodimeric transmembrane proteins that mediate cell attachment to extracellular matrix, migration, division, and inhibition of apoptosis. Because growth factors are also important for these processes, there has been interest in cooperative signaling between growth factor receptors and integrins. IGF-I is an important growth factor for vascular cells. One integrin, alphaVbeta3, that is expressed in smooth muscle cells modulates IGF-I actions. Ligand occupancy of alphaVbeta3 is required for IGF-I to stimulate cell migration and division. Src homology 2 containing tyrosine phosphatase (SHP-2) is a tyrosine phosphatase whose recruitment to signaling molecules is stimulated by growth factors including IGF-I. If alphaVbeta3 ligand occupancy is inhibited, there is no recruitment of SHP-2 to alphaVbeta3 and its transfer to downstream signaling molecules is blocked. Ligand occupancy of alphaVbeta3 stimulates tyrosine phosphorylation of the beta3-subunit, resulting in recruitment of SHP-2. This transfer is mediated by an insulin receptor substrate-1-related protein termed DOK-1. Subsequently, SHP-2 is transferred to another transmembrane protein, SHPS-1. This transfer requires IGF-I receptor-mediated tyrosine phosphorylation of SHPS-1, which contains two YXXL motifs that mediate SHP-2 binding. The transfer of SHP-2 to SHPS-1 is also required for recruitment of Shc to SHPS-1. Ligand occupancy of alphaVbeta3 results in sustained Shc phosphorylation and enhanced Shc recruitment. Shc activation results in induction of MAPK. Inhibition of the Shc/SHPS-1 complex formation results in failure to achieve sustained MAPK activation and an attenuated mitogenic response. Thus, within the vessel wall, a mechanism exists whereby ligand occupancy of the alphaVbeta3 integrin is required for assembly of a multicomponent membrane signaling complex that is necessary for cells to respond optimally to IGF-I.
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PMID:Interaction between insulin-like growth factor-I receptor and alphaVbeta3 integrin linked signaling pathways: cellular responses to changes in multiple signaling inputs. 1552 74

The endoplasmic reticulum (ER) is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER. Excessive or long-termed stresses in the ER result in apoptotic cell death involving activation of caspase-12 and -3 and the Ask-1-JNK pathway. Eukaryotic cells can adapt for survival to deal with an accumulation of unfolded proteins in the ER by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP to facilitate protein folding. The induction system is termed the unfolded protein response (UPR). It has been reported that IRE1 and PERK, transmembrane kinases, and ATF6, a transmembrane transcription factor, are mediators of the UPR through sensing accumulation of unfolded proteins. Cell fates after ER stress are regulated by the balance of both apoptosis and the UPR signaling. In the nervous systems, astrocytes are well known to be resistant to ER stresses induced by ischemia and hypoxia. These findings raise the possibility that astrocytes possess a novel UPR signaling different from that of neuronal cells. Recently, we identified a novel ER stress sensor, OASIS, which is specifically expressed in astrocytes. This protein is a transmembrane protein containing the bZIP domain. The functional analyses of OASIS showed that 1) it was cleaved within the ER membrane in response to the ER stress, 2) overexpression of OASIS induced the transcription of GRP78/BiP mRNA through the activation of cyclic AMP responsive element (CRE) and ER stress responsive element (ERSE), and 3) its stable cell lines were resistant to ER stress compared with the control cells. These results indicate that the ER-resident transcription factor OASIS may be a candidate for leading astrocytes to protect against ER stress.
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PMID:[The regulation of unfolded protein response by OASIS, a transmembrane bZIP transcription factor, in astrocytes]. 1557 42

Human CD33 is a myeloid-restricted transmembrane protein of the sialic acid-binding Ig-like lectin (Siglec) family. While structural analysis predicts an inhibitory function, it remains unknown under which circumstances CD33 may operate as an inhibitory molecule. Here we show that treatment of human monocytes with anti-CD33 mAb induces the production of the proinflammatory cytokines IL-1 beta, TNF-alpha, and IL-8. However, decreased CD33 surface expression obtained by RNA interference using cognate small interfering RNA (siRNA) was specifically paralleled by spontaneous cytokine production. Similarly, sialic acid (CD33 ligand) removal from the monocyte surface by neuraminidase resulted in IL-1 beta up-regulation, while the addition of red blood cells or sialyllactosamine (but not lactosamine) reversed the effect of neuraminidase treatment, thus demonstrating the importance of ligand recognition by CD33 for repression of monocyte activation. Finally, inhibition of phosphoinositide 3-kinase (PI3K) dramatically enhanced the IL-1 beta response to anti-CD33 and neuraminidase, while inhibition of p38 mitogen-activated protein kinase (MAPK) abolished it. Simultaneous addition of both inhibitors resulted in low levels of IL-1 beta, suggesting that CD33 exerts an inhibitory role mediated by PI3K, while p38 MAPK signaling is required for IL-1 beta production. These data indicate that by controlling monocyte activation, CD33 is a key molecule in the inflammatory response, depending on the sialic acid microenvironment for its repressor activity.
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PMID:Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. 1559 23


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