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 recent report has shown that activating mutations in the BRAF gene are present in a large percentage of human malignant melanomas and in a proportion of colon cancers. The vast majority of these mutations represent a single nucleotide change of T-A at nucleotide 1796 resulting in a valine to glutamic acid change at residue 599 within the activation segment of B-Raf. This exciting new discovery is the first time that a direct association between any RAF gene and human cancer has been reported. Raf proteins are also indirectly associated with cancer as effectors of activated Ras proteins, oncogenic forms of which are present in approximately one-third of all human cancers. BRAF and RAS mutations are rarely both present in the same cancers but the cancer types with BRAF mutations are similar to those with RAS mutations. This has been taken as evidence that the inappropriate regulation of the downstream ERKs (the p42/p44 MAP kinases) is a major contributing factor in the development of these cancers. Recent studies in mice with targeted mutations of the raf genes have confirmed that B-Raf is a far stronger activator of ERKs than its better studied Raf-1 homologue, even in cell types in which the protein is barely expressed. The explanation for this lies in a number of key differences in the regulation of B-Raf and Raf-1 activity. Constitutive phosphorylation of serine 445 of B-Raf leads to this protein having a higher basal kinase activity than Raf-1. Phosphorylation of threonine 598 and serine 601 within the activation loop of B-Raf at the plasma membrane also regulates its activity. The V599E mutation is thought to mimic these phosphorylations, resulting in a protein with high activity, leading to constitutive ERK activation. B-Raf now provides a critical new target to which drugs for treating malignant melanoma can be developed and, with this in mind, it is now important to gain clear insight into the biochemical properties of this relatively little characterised protein.
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PMID:Raf proteins and cancer: B-Raf is identified as a mutational target. 1278 69

Up to now, most of the studies addressing the critical roles played by protrusive and contractile cell-matrix contacts in cell adhesion, guidance, migration, matrix assembly, and activation of signaling molecules have been performed on two-dimensional surfaces. Here, we analysed the organization of chondrosarcoma cell contacts in a new three-dimensional environment made of titanium beads. Surface charges were modified by deposition of polyelectrolyte multilayer films built up by alternated polycations poly-(L-lysine) or poly(allylamine hydrochloride) and polyanions poly-(L-glutamic acid) or poly(sodium 4-styrenesulfonate). Negatively charged 3-D titanium surfaces amplified the occurrence and length of cell protrusions. These protrusions had pseudopod characteristics extended to 200 microm in length, growing off the substratum to distant beads. Pseudopod formation is inhibited by the exocytosis inhibitor concanamycin A and is triggered by a secreted factor. Chondrosarcoma cells adhering on uncoated or on negatively charged surfaces contained discrete focal spots of vinculin and actin cables. In cells plated onto these surfaces, phosphorylation of p44/42 MAPK/ERK was twofold increased. In contrast, no cytoskeletal vinculin and actin organization was observed when the surface was positively charged. These data suggest that chondrosarcoma cells adapt a more stable adhesion on uncoated or negatively charged surfaces. This point may be critical in tissue engineering strategies designed for cartilage repair.
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PMID:3-D surface charges modulate protrusive and contractile contacts of chondrosarcoma cells. 1456 95

A biodegradable two block copolymer, poly(epsilon-caprolactone)-b- poly(gamma-benzyl-L-glutamic acid) (PCL-PBLG) was synthesized successfully by ring-opening polymerization of N-carboxyanhydride of gamma-benzyl-L-glutamate (BLG-NCA) with aminophenyl-terminated PCL as a macroinitiator. The aminophenethoxyl-terminated PCL was prepared via hydrogenation of a 4-nitrophenethoxyl-terminated PCL, which was novelly obtained from the polymerization of epsilon-caprolactone (CL) initiated by amino calcium 4-nitrobenzoxide. The structures of the block copolymer and its precursors from the initial step of PCL were confirmed and investigated by 1H NMR, FT-IR, GPC, and FT-ICRMS analyses and DSC measurements.
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PMID:Synthesis of poly(epsilon-caprolactone)-b-poly(gamma-benzyl-L-glutamic acid) block copolymer using amino organic calcium catalyst. 1460 11

The v-raf murine sarcoma viral homolog B1 (BRAF) gene, one of the human isoforms of RAF, is activated by Ras, leading to cooperative effects in cells responsive to growth factor signals. Recently, somatic missense mutations of the BRAF gene have been detected in more than 66% of malignant melanomas of the skin. We analyzed 42 malignant melanomas of the uvea, 3 corresponding liver metastases, and 10 cutaneous melanomas for possible BRAF mutations: after microdissection, mutation analysis of BRAF and KRAS was performed. The expression of extracellular-regulated kinase 1 and 2 (ERK1/2), an important downstream point of convergence in the Ras-RAF-MEK-Erk pathway, was analyzed immunohistochemically. Interestingly, we failed to detect activating BRAF mutations in uvea melanomas and their corresponding liver metastases. There were no mutations of BRAF in corresponding non-neoplastic uvea specimens, although we detected three BRAF mutations in sporadic cutaneous melanoma that led to a substitution of valine by glutamic acid at position 599 (V599E). KRAS mutations were detected in 1 of 10 cutaneous melanoma but not in uveal or metastatic melanoma. Despite the lack of activating mutations in the BRAF gene, we identified constitutively activated ERK in almost all (86%) uveal melanoma tissues tested but not in corresponding normal retina or uveal cells. Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma. The finding of activated Erk suggests a causative role for MAPK activation in uveal melanoma independent of activating BRAF or RAS mutations.
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PMID:Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. 1469 Dec 95

A novel structural triblock copolymer of poly(gamma-benzyl-l-glutamic acid)-b-poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PBLG-PEO-PCL) was synthesized by a new approach in the following three steps: (1) sequential anionic ring opening polymerization (ROP) of ethylene oxide and epsilon-caprolactone with an acetonitrile/potassium naphthalene initiator system to obtain a diblock copolymer CN-PEO-PCL with a cyano end-group; (2) conversion of the CN end-group into NH2 end-group by hydrogenation to obtain NH2-PEO-PCL; (3) ROP of gamma-benzyl-l-glutamate-N-carboxyanhydrides (Bz-l-GluNCA) with NH2-PEO-PCL as macroinitiator to obtain the target triblock copolymer. The structures from CN-PEO precursor to the triblock copolymers were confirmed by FT-IR and 1H NMR spectroscopy, and their molecular weights were measured by gel permeation chromatography. The monomer of Bz-l-GluNCA can react almost quantitatively with the amino end-groups of NH2-PEO-PCL macroinitiator by ROP.
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PMID:Synthesis of a novel structural triblock copolymer of poly(gamma -benzyl-l-glutamic acid)-b-poly(ethylene oxide)-b-poly(epsilon-caprolactone). 1502 Jan 29

Acrosome reaction (AR) is an exocytotic process of fundamental importance for the spermatozoon to fertilize the oocyte. The mechanisms mediating this process are only partially defined. The aim of the present study was to investigate the role of various kinases and the extracellular signal-regulated kinase (ERK) pathway in the induction of the AR and associated phosphorylation of tyrosine (Tyr) residues and of the threonine-glutamic acid-tyrosine (Thr-Glu-Tyr) motif that occurs in 80 and 105 kDa proteins (p80/p105). Human spermatozoa were capacitated and AR was induced with lysophosphatidylcholine in the presence of inhibitors of various kinases and of the ERK pathway. Phosphorylation of Tyr and of Thr-Glu-Tyr peaked 15 min after the induction of the AR. Both phosphorylations were prevented by inhibitors of protein kinase C, MEK, phosphoinositide 3-kinase and Akt but not by protein kinase A inhibitors. Phosphorylation of Thr-Glu-Tyr, but not Tyr, was decreased by inhibitors of protein tyrosine kinase and Grb2-SH2. All the inhibitors prevented lysophosphatidylcholine-induced AR, indicating the involvement of PKC, PKA, PTK, PI3K, Akt and the ERK pathway. These results show that phosphorylation of Tyr and Thr-Glu-Tyr are associated with the AR and are differently regulated by the various kinases emphasing the complexity of this process.
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PMID:Various protein kinases regulate human sperm acrosome reaction and the associated phosphorylation of Tyr residues and of the Thr-Glu-Tyr motif. 1570 55

The EGFR/Ras/Raf/MEK/ERK pathway is a major pathway involved in the control of growth signals, cell survival and differentiation. Mutations of signaling components, such as EGFR (c-erbB1), Ras, and B-Raf, have been shown to play roles in the genesis of human cancer, while point mutation of ERK has not been reported. In this study, we present evidence for a mutation in an oral squamous cell carcinoma cell line, HSC6. PCR-amplification of cDNA, cloning and sequencing resulted in the identification of glutamic acid to lysine substitution at codon 322 (E322K) that occurred in the common docking (CD) domain of ERK2. The mutant protein contributed towards faster-migration in SDS-PAGE, and constitutive phosphorylation in a MEK-dependent manner. The transient transfection of the mutant ERK2 in 293T cells resulted in the expression of the same faster-migrating band in SDS-PAGE as was detected in HSC6 cells, which was preferentially phosphorylated relative to endogenous wild-type ERK2. The present study is the first to report ERK2 substitution mutation in a human cancer cell line which resulted in constitutive phosphorylation.
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PMID:A mutation in the common docking domain of ERK2 in a human cancer cell line, which was associated with its constitutive phosphorylation. 1627 4

PELP1 (proline-, glutamic acid-, and leucine-rich protein-1) (also known as the modulator of nongenomic activity of estrogen receptor) plays a role in genomic functions of the estrogen receptor via histone interactions and in nongenomic functions via its influence on the MAPK-Src pathway. However, recent studies have shown that differential compartmentalization of PELP1 could play a crucial role in modulating the status of nongenomic signaling by using molecular mechanisms that remain poorly understood. Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is an early endosomal protein that plays a role in regulating the trafficking of growth factor-receptor complexes through early endosomes. By using a yeast two-hybrid screen, we identified HRS as a novel PELP1-binding protein providing evidence of a physiologic interaction between HRS and PELP1. The noted HRS-PELP1 interaction was accompanied by inhibition of the basal coactivator function of PELP1 upon estrogen receptor transactivation. HRS was found to sequester PELP1 in the cytoplasm, leading to the activation of MAPK in a manner that is dependent on the epidermal growth factor receptor but independent of the estrogen receptor, Shc, and Src. In addition, stimulation of MAPK and the subsequent activation of its downstream effector pathway, Elk-1, by HRS or PELP1 were found to depend on the presence of endogenous PELP1 or HRS. Furthermore, HRS was overexpressed and correlated well with the cytoplasmic PELP1, increased MAPK, and EGFR status in breast tumors. These findings highlight a novel role of HRS in up-regulating MAPK, presumably involving interaction with PELP1.
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PMID:Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) interacts with PELP1 and activates MAPK. 1635 11

Mutations of genes coding effectors of signaling pathway RET/PTC-RAS-RAF-MEK-ERK, involved in cell growth and proliferation, are important in papillary thyroid cancer development. To earlier discovered mutations of RAS and RET/PTC genes, BRAF gene mutation has been recently added. Mutation of BRAF gene appears in various types of carcinomas, but most frequently in malignant melanomas (66%) and papillary thyroid cancer (average 44%). The BRAF gene protein product belongs to the serine-threonine kinase family and to the RAF proteins subfamily, among which it is the strongest activator of MAP kinases cascade. The most frequently mutation of BRAF gene is thymine to adenine transversion at nucleotide position 1796 (T1796A). This point mutation causes valine to glutamic acid substitution at residue 599 (V599E), that results in constitutive and oncogenic activation of BRAF kinase. The relation between mutations of BRAF, RAS and RET/PTC genes has not been found, although they together exist in two thirds of papillary thyroid cancers. BRAF(TI796A) oncogene appears in papillary thyroid cancer, whereas it has not been found in follicular thyroid cancer and benign thyroid adenomas. For this reason mutated BRAF gene could be specific molecular marker, with relatively high sensitivity in diagnostics of papillary thyroid cancer. In addition, BRAF gene has been demonstrated as a novel prognostic biomarker, which correlates with unfavorable clinicopathological factors, such as extrathyroidal invasion and distant metastasis.
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PMID:[BRAF gene mutation in thyroid cancer]. 1670 43

Calpain activity is required for de-adhesion of the cell body and rear to enable productive locomotion of adherent cells during wound repair and tumor invasion. Growth factors activate m-calpain (calpain 2, CAPN2) via ERK/mitogen-activated protein kinases, but only when these kinases are localized to the plasma membrane. We thus hypothesized that m-calpain is activated by epidermal growth factor (EGF) only when it is juxtaposed to the plasma membrane secondary to specific docking. Osmotic disruption of NR6 fibroblasts expressing the EGF receptor demonstrated m-calpain being complexed with the substratum-adherent membrane with this increasing in an EGF-dependent manner. m-Calpain colocalized with phosphoinositide biphosphate (PIP(2)) with exogenous phospholipase C removal of phosphoinositides, specifically, PI(4,5)P(2) but not PI(4)P(1) or PIP(3), releasing the bound m-calpain. Downregulation of phosphoinositide production by 1-butanol resulted in diminished PIP(2) in the plasma membrane and eliminated EGF-induced calpain activation. This PIP(2)-binding capacity resided in domain III of calpain, which presents a putative C2-like domain. This active conformation of this domain appears to be partially masked in the holoenzyme as both activation of m-calpain by phosphorylation at serine 50 and expression of constitutively active phosphorylation mimic glutamic acid-increased m-calpain binding to the membrane, consistent with blockade of this cascade diminishing membrane association. Importantly, we found that m-calpain was enriched toward the rear of locomoting cells, which was more pronounced in the plasma membrane footprints; EGF further enhanced this enrichment, in line with earlier reports of loss of PIP(2) in lamellipodia of motile cells. These data support a model of m-calpain binding to PIP(2) concurrent with and likely to enable ERK activation and provides a mechanism by which cell de-adhesion is directed to the cell body and tail as phospholipase C-gamma hydrolyzes PIP(2) in the protruding lamellipodia.
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PMID:Spatial localization of m-calpain to the plasma membrane by phosphoinositide biphosphate binding during epidermal growth factor receptor-mediated activation. 1680 81


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