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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A. L. Bayer, A. G. Ferguson, P. A. Lucchesi and A. M. Samarel. PYK2 Expression and Phosphorylation in Neonatal and Adult Cardiomyocytes. Journal of Molecular and Cellular Cardiology (2001) 33, 1017-1030. Proline-rich tyrosine kinase (PYK2) is a Ca(2+)-dependent, non-receptor protein tyrosine kinase involved in growth factor signaling. Although PYK2 is expressed in a variety of tissues, it has not yet been identified in cardiac muscle. Therefore, immunocytochemical and Western blotting techniques were used to examine PYK2 expression and phosphorylation in neonatal and adult rat ventricular cardiomyocytes (NRVM and ARVM, respectively). PYK2 concentration was much greater in neonatal, than in adult ventricular tissue and cardiomyocytes. In cultured cells, PYK2 expression was highly dependent on [Ca(2+)](i)transients and contractile activity. Non-contracting, low-density NRVM in serum-free culture expressed very low levels of PYK2, while high-density, spontaneously contracting NRVM showed a approximately 12-fold increase in PYK2 expression. Conversely, high-density NRVM treated with nifedipine (10 microM, 48 h) to block spontaneous [Ca(2+)](i)transients and contractile activity resulted in a 2.6-fold decrease in PYK2 levels. Similarly, overnight culture of quiescent ARVM markedly reduced PYK2 levels. Chronic treatment (48 h) of cultured NRVM with the hypertrophic agonist endothelin-1 (ET) (10-300 n M) did not significantly increase PYK2 levels, but strongly shifted the ratio of phosphorylated to total PYK2, indicating that PYK2 phosphorylation accompanies cardiomyocyte hypertrophy. Endothelin-1 also acutely activated PYK2 in both cultured NRVM, and in freshly isolated ARVM. These results suggest that PYK2 is involved in the generation of certain aspects of cardiomyocyte hypertrophy.
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PMID:Pyk2 expression and phosphorylation in neonatal and adult cardiomyocytes. 1134 23

B cell receptor (BCR) stimulation induces phosphorylation of a number of proteins, leading to functional activation of B lymphocytes. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase, involved in a variety of signaling pathways. In this study, we show that FAK is tyrosine-phosphorylated and activated following BCR stimulation. We also demonstrate constitutive association of FAK with the Src-family kinase Lyn and with components of the BCR. Association of Lyn with FAK which was not correlated with BCR-induced activation of both kinases, appeared to be mediated via the binding of Lyn to the COOH-terminal part of the FAK molecule. Our results indicate that FAK is a component of the BCR complex and that it participates in BCR signaling.
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PMID:B cell receptor signaling involves physical and functional association of FAK with Lyn and IgM. 1138 92

The c-fes locus encodes a 93-kDa non-receptor protein tyrosine kinase (Fes) that regulates the growth and differentiation of hematopoietic and vascular endothelial cells. Unique to Fes is a long N-terminal sequence with two regions of strong homology to coiled-coil oligomerization domains. We introduced leucine-to-proline substitutions into the coiled coils that were predicted to disrupt the coiled-coil structure. The resulting mutant proteins, together with wild-type Fes, were fused to green fluorescent protein and expressed in Rat-2 fibroblasts. We observed that a point mutation in the first coiled-coil domain (L145P) dramatically increased Fes tyrosine kinase and transforming activities in this cell type. In contrast, a similar point mutation in the second coiled-coil motif (L334P) was without effect. However, combining the L334P and L145P mutations reduced transforming and kinase activities by approximately 50% relative to the levels of activity produced with the L145P mutation alone. To study the effects of the coiled-coil mutations in a biologically relevant context, we expressed the mutant proteins in the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent myeloid leukemia cell line TF-1. In this cellular context, the L145P mutation induced GM-CSF independence, cell attachment, and spreading. These effects correlated with a marked increase in L145P protein autophosphorylation relative to that of wild-type Fes. In contrast, the double coiled-coil mutant protein showed greatly reduced kinase and biological activities in TF-1 cells. These data are consistent with a role for the first coiled coil in the negative regulation of kinase activity and a requirement for the second coiled coil in either oligomerization or recruitment of signaling partners. Gel filtration experiments showed that the unique N-terminal region interconverts between monomeric and oligomeric forms. Single point mutations favored oligomerization, while the double point mutant protein eluted essentially as the monomer. These data provide new evidence for coiled-coil-mediated regulation of c-Fes tyrosine kinase activity and signaling, a mechanism unique among tyrosine kinases.
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PMID:A point mutation in the N-terminal coiled-coil domain releases c-Fes tyrosine kinase activity and survival signaling in myeloid leukemia cells. 1150 60

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase localized at focal adhesions and is believed to mediate adhesion-stimulated effects. Although ablation of FAK impairs cell movement, it is not clear whether FAK might be involved in the guidance of cell migration, a role consistent with its putative regulatory function. We have transfected FAK-null fibroblasts with FAK gene under the control of the tetracycline repression system. Cells were cultured on flexible polyacrylamide substrates for the detection of traction forces and the application of mechanical stimulation. Compared with control cells expressing wild-type FAK, FAK-null cells showed a decrease in migration speed and directional persistence. In addition, whereas FAK-expressing cells responded to exerted forces by reorienting their movements and forming prominent focal adhesions, FAK-null cells failed to show such responses. Furthermore, FAK-null cells showed impaired responses to decreases in substrate flexibility, which causes control cells to generate weaker traction forces and migrate away from soft substrates. Cells expressing Y397F FAK, which cannot be phosphorylated at a key tyrosine site, showed similar defects in migration pattern and force-induced reorientation as did FAK-null cells. However, other aspects of F397-FAK cells, including the responses to substrate flexibility and the amplification of focal adhesions upon mechanical stimulation, were similar to that of control cells. Our results suggest that FAK plays an important role in the response of migrating cells to mechanical input. In addition, phosphorylation at Tyr-397 is required for some, but not all, of the functions of FAK in cell migration.
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PMID:Focal adhesion kinase is involved in mechanosensing during fibroblast migration. 1157 81

When a transmembrane receptor protein tyrosine kinase (RTK) is expressed throughout the plasma membrane, yet only a specific handful of them must be activated, what's a ligand to do? During the development of the anterior and posterior termini of the Drosophila embryo, uniformly secreted ligand precursors are activated by proteolysis near the location of the receptors that must be activated. Stein and Stevens discuss the recent publication by Casali and Casanova that describes the mechanism of activation of the Drosophila RTK called Torso. In addition, Casali and Casanova may have identified a physiologically relevant ligand for Torso called Trunk. Proteolytic cleavage of the Trunk precursor can activate Torso-dependent signaling, but the existence of cleaved Trunk has not yet been demonstrated in vivo for Drosophila. Stein and Stevens discuss the ramifications of such a highly regulated process of ligand activation, and also prefer alternative scenarios for Torso activation.
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PMID:The torso ligand, unmasked? 1175 76

We have recently shown that the hormonal form of vitamin D3, 1,25(OH)2-vitamin D3 (1,25(OH)2D3), stimulates the enzymatic activity of the non-receptor protein tyrosine kinase c-Src in skeletal muscle cells. In this study we show that intracellular and extracellular Ca2+ chelation with BAPTA and EGTA, respectively, blocked hormone stimulation of c-Src activity/dephosphorylation, indicating that the calcium messenger system is an upstream activator of c-Src. Tyrosine phosphorylation and stimulation of the growth-related mitogen-activated protein kinase (MAPK) by 1,25(OH)2D3 was shown to be dependent on activation of c-Src, since pretreatment with the c-Src specific inhibitor PP1 or muscle cell transfection with an antisense oligodeoxynucleotide directed against c-Src mRNA markedly reduced hormone stimulation of MAPK phosphorylation. Evidence was obtained indicating that MAPK is then translocated to the cell nucleus in active phosphorylated form and induces the expression of c-myc oncoprotein, as the MAPK kinase (MEK) inhibitor PD98059 abolished stimulation of c-myc synthesis by 1,25(OH)2D3. In addition, the hormone rapidly stimulated tyrosine phosphorylation of c-myc. In cells pretreated with PP1 (4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo-D3,4-pyrimidine), the 1,25(OH)2D3-induced increase in tyrosine phosphorylation of c-myc was suppressed. Taken together, these results demonstrate that 1,25(OH)2D3 stimulates proliferation-associated signalling pathways in skeletal muscle cells and implicate c-Src kinase as mediator of this response.
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PMID:The tyrosine kinase c-Src is required for 1,25(OH)2-vitamin D3 signalling to the nucleus in muscle cells. 1175 12

PTK6 (also known as Brk) is a non-receptor protein tyrosine kinase, whose mRNA was expressed in the limited normal tissues such as colon and small intestine, and in breast carcinomas and breast cancer cell lines. The 813 bp region upstream from the translation initiation codon, which constitutes a functional promoter of the human PTK6 gene, was progressively deleted and fused to the luciferase reporter gene and transient expression of the resultant constructs was measured upon transfection into a breast carcinoma cell line, T-47D. Comparative analysis of luciferase activity revealed two major regions, -93 to -76 and -702 to -655, important for transcriptional regulation. The proximal -93 to -76 region was found to be essential for the function of the minimal promoter. By primer extension and PCR, it was shown that a PTK6 transcript started at the most 5' upstream is located around base -104. Therefore, the proximal -93 to -76 region is thought to function as a downstream cis-acting element. Luciferase analysis showed that the distal -702 to -655 region contained at least two cis-acting elements. Gel mobility shift assays with T-47D nuclear extract including competition analyses with consensus and mutant oligonucleotides and supershift analyses with NF-kappaB and Sp1 antibodies showed that NF-kappaB binds to the sequence from -706 to -688 and Sp1 binds to the sequence from -688 to -669. This study thus provides the first molecular insights into the transcriptional regulation of the human PTK6 gene.
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PMID:Characterization of the 5'-flanking region of the human PTK6 gene. 1199 4

Trastuzumab, a monoclonal antibody that is selective for cells that overexpress the erbB2 receptor protein tyrosine kinase, is a promising targeted therapy for the treatment of breast cancer. Surprisingly, toxic cardiovascular side effects were discovered in late-phase clinical trials, and these effects were most prominent when trastuzumab was combined with anthracycline chemotherapy. We review recent data focusing on how erbB2 monoclonal antibodies could exert a cardiotoxic effect through unique cardiomyocyte cell surface and intracellular structural features, and how an individual's cardiac susceptibility to erbB2 monoclonal antibodies may be dictated by the ability of erbB2 monoclonal antibodies to bind cardiomyocytes. In addition, we discuss ways that anthracyclines may also affect erbB2/erbB4/neuregulin receptor signaling, explaining the apparent synergistic effect. Further investigation of the role of normal and aberrant erbB2 signaling in the development of cardiac dysfunction could lead to an improved understanding of the pathophysiology of cardiac dysfunction and may lead to novel therapies for the treatment of heart failure, regardless of etiology. Understanding the nature and specificity of trastuzumab's cardiotoxic effects is important in better defining clinical criteria for inclusion and exclusion of patients who can safely receive trastuzumab for the treatment of breast cancer, or possibly other malignancies.
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PMID:Trastuzumab cardiotoxicity: Speculations regarding pathophysiology and targets for further study. 1213 94

The phagocytosis of photoreceptor outer segments by retinal pigment epithelial (RPE) cells plays a critical role in preserving normal retinal function. Recently the receptor protein tyrosine kinase (RTK) Mer, has been shown to be necessary for this cellular process to take place. Gas6, the ligand for the Mer RTK, can specifically and selectively stimulate the phagocytosis of photoreceptor outer segments (OS) by normal cultured rat RPE cells, as we have previously reported. The Gas6 protein has been shown to associate with plasma membrane phosphatidylserine by its amino-terminal portion, while its carboxyl-terminal portion can bind and activate Mer and its related RTKs, Axl and Tyro-3. Given the capability of Gas6 to interact with more than one molecule, we have performed a series of experiments to further dissect the interactions of Gas6 with the OS and RPE and to determine the specific calcium requirements necessary for Gas6 to exert its stimulatory effect on phagocytosis. These experiments show that Gas6 must bind to OS before the stimulation of OS ingestion can occur and that this binding requires a Ca(2+) concentration of 500-600 microM. The same Ca(2+) concentration is required for the Gas6 mediated stimulation of OS ingestion. We further demonstrate that in order to bind to OS and to stimulate OS phagocytosis, Gas6 requires gamma-carboxylation in a vitamin K-dependent reaction. By analogy with other systems, we propose that Ca(2+) mediates the linkage between the gamma-carboxyglutamic acid (Gla)-rich N-terminal region of Gas6 with phospholipids, presumably phosphatidylserine, in the plasma membrane of the OS. Only after this binding has occurred can Gas6 interact with receptor molecule(s) on the surface of the RPE, and activate RPE cell signaling pathways leading to OS ingestion. These studies further underscore the importance of Gas6 in the phagocytic function of the RPE and open new avenues of investigation to understand the molecular events mediated and triggered by Gas6, and its interaction with the OS and RPE.
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PMID:Gas6 binding to photoreceptor outer segments requires gamma-carboxyglutamic acid (Gla) and Ca(2+) and is required for OS phagocytosis by RPE cells in vitro. 1238 86

Src is a non-receptor protein tyrosine kinase, the expression and activity of which is increased in >80% of human colon cancers with respect to normal colonic epithelium. Previous studies from this and other laboratories have demonstrated that Src activity contributes to tumorigenicity of established colon adenocarcinoma cell lines. Src participates in the regulation of many signal transduction pathways, among which are those leading to cellular survival. In this study, we addressed the potential role of Src activation to a specific aspect of tumor cell survival, resistance to detachment-induced apoptosis (anoikis). Using five colon tumor cell lines with different biologic properties and genetic alterations, we demonstrate that expression and activity of Src corresponds with resistance to anoikis. Enforced expression of activated Src in subclones of SW480 cells (of low intrinsic Src expression and activity) increases resistance to anoikis; whereas decreased Src expression in HT29 cells (of high Src expression and activity) by transfection with anti-sense Src expression vectors increases susceptibility to anoikis. In contrast, increasing or decreasing Src expression had no effect on susceptibility to staurosporine-induced apoptosis in attached cells. PD173955, a Src family-specific tyrosine kinase inhibitor, increases the susceptibility of HT29 cells to anoikis in a dose- and time-dependent manner. Increasing Src expression and activity led to increased phosphorylation of Akt, a mediator of cellular survival pathways, whereas decreasing Src activity led to decreased Akt phosphorylation. In colon tumor cells with high Src activity, the PI3 kinase inhibitor LY 294002 sensitized cells to anoikis. These results suggest that Src activation may contribute to colon tumor progression and metastasis in part by activating Akt-mediated survival pathways that decrease sensitivity of detached cells to anoikis.
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PMID:Src activation regulates anoikis in human colon tumor cell lines. 1242 Feb 16


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