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)

Cofilin is a widely-distributed, intracellular, actin binding protein which is involved in the translocation of actin-cofilin complex from cytoplasm to nucleus. We have cloned a non-muscle-type cofilin (CFL1) from a human promyelocytic cDNA library and mapped this to human chromosome 11 by PCR amplification of 3' untranslated sequence in a panel of rodent-human somatic cell hybrids, and to the interval 11q12-q13.2 in a chromosome 11 somatic cell hybrid mapping panel. Confirmation of regional localisation to 11q13 has been obtained by fluorescent in situ hybridisation of genomic cosmid clones, by demonstration of the presence of both SEA (the human homologue of avian retrovirus proviral tyrosine kinase, 11q13) and CFL1 in some of these clones and by close linkage of CFL1 to SEA in a panel of high-dose irradiation hybrids. We have identified human muscle-type cofilin sequences by comparison of human expressed sequence tags with M-type cofilins of other species and we have mapped the human M-type cofilin, CFL2, to chromosome 14.
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PMID:Mapping of human non-muscle type cofilin (CFL1) to chromosome 11q13 and muscle-type cofilin (CFL2) to chromosome 14. 880 Apr 36

Cellular transformation by v-Src is believed to be caused by aberrant activation of signaling pathways that are normally regulated by cellular Src. Using normal rat kidney cells expressing a temperature-sensitive mutant of v-Src, we examined the role of the Raf/MEK/ERK, phosphatidylinositol 3-kinase/Akt, and Rho pathways in morphological transformation and cytoskeletal changes induced by v-Src. Activation of v-Src elicited a loss of actin stress fibers and focal contacts. A decrease in the phosphorylation level of cofilin was detected upon v-Src activation, which is indicative of attenuated Rho function. Inhibition of MEK using U0126 prevented v-Src-induced disruption of the cytoskeleton as well as dephosphorylation of cofilin, whereas treatment with a phosphatidylinositol 3-kinase inhibitor had no protective effect. In normal rat kidney cells stably transformed by v-Src, we found that the chronic activation of MEK induces down-regulation of ROCK expression, thereby uncoupling Rho from stress fiber formation. Taken together, these results establish MEK as an effector of v-Src-induced cytoskeleton disruption, participating in v-Src-induced antagonism of the cellular function of Rho.
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PMID:MEK mediates v-Src-induced disruption of the actin cytoskeleton via inactivation of the Rho-ROCK-LIM kinase pathway. 1201 Oct 49

Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A- and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-alpha6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype.
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PMID:Characterization of gene expression induced by RET with MEN2A or MEN2B mutation. 1210 9

The genetically selected long attack latency (LAL) and short attack latency (SAL) mice differ in a wide variety of behavioural traits and display differences in the serotonergic system and the hypothalamus-pituitary-adrenocortical (HPA)-axis. Serial analysis of gene expression (SAGE) was used to generate a hippocampal expression profile of almost 30 000 genes in LAL and SAL mice. Using SAGE, we found differential expression of 191 genes. Among these were genes involved in growth, signal transduction, and cell metabolism. The SAGE study was supported by GeneChip analysis (Affymetrix). Strikingly, both SAGE and GeneChips showed a higher expression of numerous cytoskeleton genes, such as cofilin and several tubulin isotypes in LAL mice. LAL mice also showed a higher expression of several calmodulin-related genes and genes encoding components of a MAPK cascade, namely raf-related oncogene and ERK2. The findings were confirmed by in situ hybridization. Our results of differential expression of cytoskeleton and signal transduction genes therefore suggest differential regulation of the raf/ERK pathway that may be related to structural differences in the hippocampus of LAL and SAL mice. As stress-related disorders, such as depression, are also linked to differential regulation of the HPA-axis and the serotonergic system and are associated with altered hippocampal morphology, differential regulation of these genes may be involved in the pathogenesis of these diseases.
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PMID:Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice. 1254 75

We previously reported that the Rho-Rho kinase pathway controls cyclin D1 expression by preventing its early G1 phase induction in response to Rac and/or Cdc42, thus increasing its dependence on ERK signaling and actin stress fiber formation. We now show that the Rho kinase effector LIM kinase is responsible for this effect. Surprisingly, inhibition of Rac-dependent cyclin D1 expression by LIM kinase is independent of both cofilin phosphorylation and actin polymerization. Instead, specific mutation of its nuclear localization and export sequences showed that LIM kinase acts in the nucleus to suppress Rac/Cdc42-dependent cyclin D1 expression. Our results therefore describe an unexpected role for LIM kinase that requires nuclear translocation. The effect of nuclear LIM kinase on cyclin D1 expression ultimately regulates the duration of G1 phase and the degree to which G1 phase progression depends on actin stress fiber formation and imposition of cellular tension.
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PMID:Nuclear translocation of LIM kinase mediates Rho-Rho kinase regulation of cyclin D1 expression. 1764 1

Differing spatial scales of signaling cascades are critical for cell orientation during chemotactic responses. We used biotin EGF bound to streptavidin-coupled magnetic beads to locally stimulate cells overexpressing the EGF receptor. We have found that EGF-induced actin polymerization remains localized even under conditions of receptor overexpression. Conversely, EGF-induced ERK activation spreads throughout the cell body after EGF bead stimulation. The localized actin polymerization is independent of PI3-kinase and rho protein activity and requires Arp2/3 complex and cofilin function. Thus, we find differing spatial scales of signaling from the EGF receptor, supporting models of chemotaxis that integrate short- and long-range signaling.
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PMID:Local signaling by the EGF receptor. 1295 32

Recent data have shown that the BRAF gene is mutated at a high frequency in human malignancies. We have analyzed the migratory characteristics of B-raf(-/-) mouse embryonic fibroblasts (MEFs) and compared these with the organization of the actin cytoskeleton and the activity of signaling pathways that are known to influence this organization. Disruption of B-raf significantly reduced the levels of phospho-ERK1/2 and, surprisingly, induced an approximately 1.5-fold increase in cell migration. Consistent with these findings, the high level of actin stress fibers normally present in MEFs was considerably reduced following disruption of B-raf, and the F-actin content of B-raf(-/-) cells was less than half that of B-raf(+/+) cells. Phosphorylation of the myosin light chain on Thr18/Ser19 residues was not reduced in B-raf(-/-) cells. Rather, reduced ROCKII expression and attenuated phosphorylation of ADF/cofilin on serine 3 occurred. Normal stress fiber and phosphocofilin levels were restored by the expression of human B-Raf and catalytically active MEK and by the overexpression of LIM kinase (LIMK). These results have important implications for the role of the B-Raf/ERK signaling pathway in regulating cell motility in normal and malignant cells. They suggest that B-Raf is involved in invasiveness by regulating the proper assembly of actin stress fibers and contractility through a ROCKII/LIMK/cofilin signaling pathway.
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PMID:B-Raf acts via the ROCKII/LIMK/cofilin pathway to maintain actin stress fibers in fibroblasts. 1519 48

We have investigated transforming growth factor beta (TGF-beta)-mediated induction of actin stress fibers in normal and metastatic epithelial cells. We found that stress fiber formation requires de novo protein synthesis, p38Mapk and Smad signaling. We show that TGF-beta via Smad and p38Mapk up-regulates expression of actin-binding proteins including high-molecular-weight tropomyosins, alpha-actinin and calponin h2. We demonstrate that, among these proteins, tropomyosins are both necessary and sufficient for TGF-beta induction of stress fibers. Silencing of tropomyosins with short interfering RNAs (siRNAs) blocks stress fiber assembly, whereas ectopic expression of tropomyosins results in stress fibers. Ectopic-expression and siRNA experiments show that Smads mediate induction of tropomyosins and stress fibers. Interestingly, TGF-beta induction of stress fibers was not accompanied by changes in the levels of cofilin phosphorylation. TGF-beta induction of tropomyosins and stress fibers are significantly inhibited by Ras-ERK signaling in metastatic breast cancer cells. Inhibition of the Ras-ERK pathway restores TGF-beta induction of tropomyosins and stress fibers and thereby reduces cell motility. These results suggest that induction of tropomyosins and stress fibers play an essential role in TGF-beta control of cell motility, and the loss of this TGF-beta response is a critical step in the acquisition of metastatic phenotype by tumor cells.
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PMID:A critical role of tropomyosins in TGF-beta regulation of the actin cytoskeleton and cell motility in epithelial cells. 1531 45

Actin cytoskeleton reorganization is regulated by various actin-binding proteins. Cofilin is the principal filament-depolymerizing protein, whose activity is reduced upon phosphorylation by LIMK. Thus, LIMK and cofilin comprise a signal transduction module regulating actin turnover and myogenic tone in healthy vasculature. Novel functions of smooth muscle cells (SMCs) in the hypertensive pulmonary artery, such as increased motility and proliferation, are supported by the actin cytoskeleton. We therefore hypothesized that bioactive peptides that affect these SMC functions may also result in an upregulation of LIMK and cofilin expression. Semiquantitative RT-PCR and immunoblotting indicated that LIMK2 and cofilin mRNA and protein expression is upregulated in canine pulmonary artery SMCs (PASMCs) exposed to PDGF or IL-1beta (10 ng/ml). Inhibition of ERK MAPKs (U-0126, 10 muM) or p38 MAPK (PD-169316, 10 muM), but not PI3Ks (LY-294002, 50 muM), reduced LIMK2 and cofilin gene expression stimulated by PDGF or IL-1beta. Inhibition of ROCK (Y-27632, 10 muM) reduced only the IL-1beta-stimulated LIMK2 and cofilin expression. These novel observations in PASMCs indicate that LIMK2 and cofilin expression can be induced by PDGF or IL-1beta. This parallel upregulation of LIMK2 and cofilin may have potentially broad functional significance for the progress of pulmonary artery disease.
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PMID:PDGF and IL-1beta upregulate cofilin and LIMK2 in canine cultured pulmonary artery smooth muscle cells. 1546

Integrin-mediated cell adhesion induces activation of the EGF receptor tyrosine kinase independently of the soluble growth factor ligand. EGFR activation is instrumental for subsequent activation of additional signaling pathways in adherent cells, including the Ras-MAP kinase pathway and the phosphatidylinositol 3-kinase/Akt pathway. We demonstrate here that integrin-dependent EGFR activation is also essential for adhesion-induced formation of actin stress fibers, focal adhesion localization and tyrosine phosphorylation of the adapter protein paxillin, as well as transcriptional activation of the serum response factor. All these events are known to be mediated by the small GTPase RhoA. EGFR activity was not found to regulate the activity status of RhoA, however. Instead, we found that EGFR activity is required for integrin-induced phosphorylation of cofilin. Cofilin is an actin-binding protein, which, when unphosphorylated, stimulates depolymerization and severing of actin filaments. Thus, in the absence of the kinase activity of the EGFR, cofilin remains dephosphorylated and depolymerizes actin filaments, rendering cells unable to respond to RhoA signaling. These studies demonstrate adhesion-dependent regulation of cofilin phosphorylation, and identify a novel role for EGFR in integrin signaling.
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PMID:EGF receptor activity is essential for adhesion-induced stress fiber formation and cofilin phosphorylation. 1612 57


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