Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Grb2, composed entirely of SH2 and SH3 domains, serves as an adaptor protein in signaling from growth factor-activated tyrosine kinase receptors. It interacts via its SH2 domain with the autophosphorylated carboxyl-terminal tail of activated epidermal growth factor (EGF) receptor and via its SH3 domains with proline-rich sequences in the Ras guanine nucleotide releasing factor, Son of sevenless (Sos). Recruitment of the Grb2-Sos complex to the receptor upon its stimulation leads to Ras activation. A major question remains as to whether SH2-mediated binding of Grb2 to the activated receptor results in conformational changes that influence its SH3-mediated association with Sos, thereby affecting Sos activity. This question is addressed through studies of the binding to intact Grb2 of an EGF receptor-derived phosphotyrosine-containing peptide and a Sos-derived proline-rich peptide using isothermal titration calorimetry and surface plasmon resonance measurements. The phosphopeptide binds to Grb2 in a 1:1 complex, with a KD of 0.4 microns. The Sos proline-rich peptide binds to Grb2 in a 2:1 complex, with a KD of 22 microns. Saturation of the SH2 domain of Grb2 with the EGFR phosphopeptide was found not to affect its subsequent binding to the Sos peptide. Thus we detected no influence of SH2 binding upon SH3-mediated interactions, suggesting that the domains do not communicate, and that recruitment itself of Sos to the cell surface is sufficient for Ras signaling.
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PMID:Independent binding of peptide ligands to the SH2 and SH3 domains of Grb2. 752 91

To identify genes involved in signal transduction pathways that regulate T cell activation and development, murine fetal thymocytes were screened for expression of protein tyrosine kinase family members by the polymerase chain reaction. Using this approach, a non-receptor protein tyrosine kinase, txk, was identified and cloned. Tsk is expressed in thymocytes as early as fetal day 13.5 and its expression at the mRNA level continues throughout development. Txk transcripts are present in thymocytes, peripheral T cells and mast cell lines, but are not detectable in B cell macrophage/monocyte cell lines or in non-hematopoietic fetal or adult tissues. In both thymocytes and T cells, txk transcripts are down-regulated after activation with PMA and ionomycin, concanavalin A or T cell receptor cross-linking. Sequence analysis indicates that txk contains SH2, SH3 and kinase catalytic domains and belongs to the tec family of cytoplasmic protein tyrosine kinases which includes tec, itk and btk. Its unique N-terminus contains a proline-rich region, but unlike the other tec family members, does not contain a pleckstrin homology domain. The restricted expression pattern of txk and its regulation by T cell activation make it an excellent candidate for involvement in signal transduction during thymocyte development.
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PMID:Murine txk: a protein tyrosine kinase gene regulated by T cell activation. 754 61

The complete amino acid sequence of a lectin-related 16.5-kDa protein (PCL-RP) isolated from fruit bodies of a lectin-deficient strain of P. cornucopiae is presented. The sequences of six out of the seven peptides generated by digestion with lysylendopeptidase and four of the five peptides generated by cyanogen bromide cleavage were completely analyzed. Overlapping peptides were obtained by arginylendopeptidase digestion. PCL-RP was a single-chain protein consisting of 144 amino acid residues and its N-terminal serine was blocked with acetate. A proline-rich sequence was found in the carboxyl terminal portion. The N-terminal sequence of PCL-RP showed some homology with those of two known Basidiomycete lectins.
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PMID:Complete amino acid sequence of a lectin-related 16.5-kDa protein isolated from fruit bodies of a lectin-deficient strain of Pleurotus cornucopiae. 762 42

SPRK (also called PTK-1 and MLK-3), a member of the mixed lineage kinase subfamily of (Ser/Thr) protein kinases, encodes an amino-terminal SH3 domain followed by a kinase catalytic domain, two leucine zippers interrupted by a short spacer, a Rac/Cdc42 binding domain, and a long carboxyl-terminal proline-rich region. We report herein that SPRK activates the stress-activated protein kinases (SAPKs) but not ERK-1 during transient expression in COS cells; the p38 kinase is activated modestly (1.3-2 fold) but consistently. SPRK also activates cotransfected SEK-1/MKK-4, a dual specificity kinase which phosphorylates and activates SAPK. Reciprocally, expression of mutant, inactive SEK-1 inhibits completely the basal and SPRK-activated SAPK activity. Immunoprecipitated recombinant SPRK is able to phosphorylate and activate recombinant SEK-1 in vitro to an extent comparable to that achieved by MEK kinase-1. These results identify SPRK as a candidate upstream activator of the stress-activated protein kinases, acting through the phosphorylation and activation of SEK-1.
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PMID:The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1. 870 71

Mitogen-activated protein kinases (MAPKs) are components of sequential kinase cascades that are activated in response to a variety of extracellular signals. Members of the MAPK family include the extracellular response kinases (ERKs or p42/44(MAPK)), the c-Jun amino-terminal kinases (JNKs), and the p38/Hog 1 protein kinases. MAPKs are phosphorylated and activated by MAPK kinases (MKKs or MEKs), which in turn are phosphorylated and activated by MKK/MEK kinases (Raf and MKKK/MEKKs). We have isolated two cDNAs encoding splice variants of a novel MEK kinase, MEKK4. The MEKK4 mRNA is widely expressed in mouse tissues and encodes for a protein of approximately 180 kDa. The MEKK4 carboxyl-terminal catalytic domain is approximately 55% homologous to the catalytic domains of MEKKs 1, 2, and 3. The amino-terminal region of MEKK4 has little sequence homology to the previously cloned MEKK proteins. MEKK4 specifically activates the JNK pathway but not ERKs or p38, distinguishing it from MEKKs 1, 2 and 3, which are capable of activating the ERK pathway. MEKK4 is localized in a perinuclear, vesicular compartment similar to the Golgi. MEKK4 binds to Cdc42 and Rac; kinase-inactive mutants of MEKK4 block Cdc42/Rac stimulation of the JNK pathway. MEKK4 has a putative pleckstrin homology domain and a proline-rich motif, suggesting specific regulatory functions different from those of the previously characterized MEKKs.
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PMID:Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. 907 50

We have characterized signaling pathways involving the related adhesion focal tyrosine kinase (RAFTK, also known as PYK2 or CAK-beta) in CMK human megakaryocytic cells. Stem cell factor, which potentiates the growth of megakaryocytes and their progenitors, and phorbol myristate acetate, which causes differentiation of megakaryocytic cell lines, induced the tyrosine phosphorylation of RAFTK but not of focal adhesion kinase. Stimulation of CMK cells with stem cell factor resulted in an increase in the autophosphorylation and kinase activity of RAFTK. Phosphorylation of RAFTK under these conditions was mediated by a protein kinase C-dependent pathway. Cytochalasin D, which disrupts the cytoskeleton, abolished the phosphorylation of RAFTK upon phorbol myristate acetate and stem cell factor stimulation, indicating that RAFTK association with the actin cytoskeleton appears to be critical for its phosphorylation. In addition, we observed an association of RAFTK with paxillin, a 68-kDa cytoskeleton protein. Using in vitro binding assays, RAFTK and paxillin were shown to bind directly through the C-terminal proline-rich domain. Transient overexpression of a dominant-negative mutant of RAFTK inhibited significantly the tyrosine phosphorylation of paxillin upon phorbol myristate acetate stimulation. These observations indicate that RAFTK might play an important role in the phosphorylation of signaling pathways within the focal adhesions and that RAFTK participates in signaling events that link signals from the cell surface to the cytoskeleton. Furthermore, this study suggests that RAFTK might be involved in megakaryocyte proliferation and differentiation.
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PMID:Tyrosine phosphorylation of the related adhesion focal tyrosine kinase in megakaryocytes upon stem cell factor and phorbol myristate acetate stimulation and its association with paxillin. 909 34

The mig-10 gene of Caenorhabditis elegans is required for the long-range anteroposterior migration of embryonic neurons CAN, ALM, and HSN and proper development of the excretory canals. Here, we report the cloning and initial molecular characterization of mig-10. The predicted MIG-10 proteins share a large region of similarity with a recently identified family of mammalian SH2 domain proteins, Grb7 and Grb10. We call this region of similarity the GM region (for Grb and Mig). MIG-10 proteins do not contain an SH2 domain, but share with the Grbs a pleckstrin homology (PH) domain and proline-rich regions, features commonly found in signal transduction proteins. The functions of Grb7 and Grb10 are unknown, but Grb7 is overexpressed in certain breast cancers, where it is bound to the growth factor receptor HER2, while Grb10 has been implicated in insulin signaling. We also report the isolation of a new mig-10(e2527) allele, as well as the molecular characterization of e2527 (splice acceptor mutation) and the canonical ct41 (amber) allele. Finally, we report the results of a genetic mosaic analysis which reveal that mig-10 acts cell nonautonomously in the development of the excretory canals and suggest a possible focus for mig-10 activity within descendants of the AB cell lineage. Elucidation of the role of mig-10 in C. elegans development should lead to a better understanding of cell migration and may shed light on the function of a family of SH2 domain proteins apparently involved in signal transduction and cancer.
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PMID:C. elegans cell migration gene mig-10 shares similarities with a family of SH2 domain proteins and acts cell nonautonomously in excretory canal development. 914 91

We have identified a new gene, designated lok (lymphocyte-oriented kinase), that encodes a 966-amino acid protein kinase whose catalytic domain at the N terminus shows homology to that of the STE20 family members involved in mitogen-activated protein (MAP) kinase cascades. The non-catalytic domain of LOK does not have any similarity to that of other known members of the family. There is a proline-rich motif with Src homology region 3 binding potential, followed by a long coiled-coil structure at the C terminus. LOK is expressed as a 130-kDa protein, which was detected predominantly in lymphoid organs such as spleen, thymus, and bone marrow, in contrast to other mammalian members of the STE20 family. LOK phosphorylated itself as well as substrates such as myelin basic protein and histone IIA on serine and threonine residues but not on tyrosine residues, establishing LOK as a novel serine/threonine kinase. When coexpressed in COS7 cells with the known MAP kinase isoforms (ERK, JNK, and p38), LOK activated none of them in contrast to PAK- and GCK-related kinases. These results suggest that LOK could be involved in a novel signaling pathway in lymphocytes, which is distinct from the known MAP kinase cascades.
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PMID:LOK is a novel mouse STE20-like protein kinase that is expressed predominantly in lymphocytes. 927 26

Human bone marrow endothelial cells immortalized with the T antigen of SV40 (TrHBMEC) have previously been characterized by us with regard to their properties that are similar to primary marrow endothelial cells and their utility as a model system. We now report that TrHBMEC express a recently discovered signal transduction molecule termed RAFTK (related adhesion focal tyrosine kinase), also called Pyk2 or CAK-beta. RAFTK, the second member of the focal adhesion kinase (FAK) family, is known to be activated in response to calcium flux in neuronal cells and integrin stimulation in megakaryocytes and B cells. We have studied the effects of cytokines on RAFTK activation in TrHBMEC. Treatment of TrHBMEC with the vascular endothelial growth factor (VEGF), as well as the VEGF-related protein (VRP), the recently identified ligand for the FLT-4 receptor, resulted in enhanced tyrosine phosphorylation of RAFTK. Similar changes in RAFTK phosphorylation were observed upon stimulation of TrHBMEC with basic fibroblast growth factor (bFGF) or oncostatin M (OSM). Stimulation of these cells with growth factors also resulted in an increase in RAFTK activity and the c-Jun NH2-terminal kinase (JNK). RAFTK coimmunoprecipitated with the cytoskeletal protein paxillin through its C-terminal proline-rich domain in TrHBMEC. These results suggest that, in marrow endothelium, activation of RAFTK by VEGF, VRP, OSM, and bFGF represents a new element in the signal transduction pathways used by these growth factors and likely acts to coordinate signaling from their surface receptors to the cytoskeleton, thereby modulating cell growth and function.
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PMID:Characterization of signal transduction pathways in human bone marrow endothelial cells. 931 Apr 76

Apoptosis, or programmed cell death, is a process where developmental or environmental stimuli activate a genetic program to implement a series of events that culminate in cell death. To study the nature of genes that are induced during the apoptotic death of myeloid precursor cells, we utilized the 32Dcl3 cell line, which is derived from normal mouse bone marrow, is non-tumorigenic and diploid. These cells are strictly dependent on IL-3 for growth and apoptose when deprived of IL-3. However, when these cells are transferred to medium containing G-CSF, the cell number increases 4-5-fold and after 12 days the entire population is differentiated into granulocytes followed by apoptotic death. In our search for genes that are induced during apoptosis and/or terminal differentiation of 32Dcl3 cells, we identified a novel gene termed AATYK (Apoptosis Associated Tyrosine Kinase), whose expression is dramatically upregulated during IL-3 deprivation as well as G-CSF-induced terminal differentiation. In this report, we describe the sequence of the cDNA clone, derived from the mRNA transcript of this gene. These studies show that this gene encodes a protein with a tyrosine kinase domain at the N-terminal end and a proline-rich domain at the C-terminal end. We also report that the expression of this gene is blocked in v-abl or bcr-abl transformed myeloid cells which are unable to apoptose when grown in the absence of IL-3. However, AATYK expression is induced in 32D cells transformed by the v-abl gene when these cells are incubated in the presence of DMSO, which induces growth arrest and apoptotic death of the cells. On the other hand, DMSO fails to induce apoptosis or AATYK expression in 32D cells transformed by the bcr-abl oncogene, suggesting that AATYK expression may be a necessary pre-requisite for the induction of growth arrest and/or apoptosis of myeloid precursor cells.
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PMID:AATYK: a novel tyrosine kinase induced during growth arrest and apoptosis of myeloid cells. 944 61


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