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

---

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

Interleukin-1 (IL-1) signaling is dependent on focal adhesions, structures that are enriched with tyrosine kinases and phosphatases. Because the non-receptor tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) is enriched in focal adhesions and IL-1-induced ERK activation requires increased Ca(2+), we determined whether SHP-2 modulates IL-1-induced Ca(2+) signaling. In SHP-2-deficient fibroblasts, IL-1-induced Ca(2+) signaling and ERK activation were markedly diminished compared with cells expressing SHP-2. IL-1-induced Ca(2+) release from the endoplasmic reticulum occurred in the vicinity of focal adhesions and was strongly inhibited by the blockage of phospholipase C (PLC) catalytic activity. Immunoprecipitation and immunostaining showed that SHP-2, the endoplasmic reticulum-specific protein calnexin, and PLCgamma1 were associated with focal adhesions; however, these associations and IL-1-induced ERK activation dissipated after cells were plated on non-integrin substrates. IL-1 promoted phosphorylation of SHP-2 and PLCgamma1. IL-1-induced phosphorylation of PLCgamma1 was diminished in SHP-2-deficient cells but was restored by stable transfection with SHP-2. BAPTA/AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)) blocked IL-1-induced phosphorylation of SHP-2 and PLCgamma1, indicating mutually dependent interactive roles for Ca(2+), SHP-2, and PLCgamma1 in IL-1 signaling. We conclude that SHP-2 is critical for IL-1-induced phosphorylation of PLCgamma1 and thereby enhances IL-1-induced Ca(2+) release and ERK activation. Focal adhesions co-localizing with the endoplasmic reticulum may provide molecular staging sites required for ERK activation.
...
PMID:SHP-2 modulates interleukin-1-induced Ca2+ flux and ERK activation via phosphorylation of phospholipase Cgamma1. 1556 58

It has been demonstrated that exposure to cocaine increases cell death in the fetal CNS. To examine the molecular mechanisms of this effect, we employed mouse oligo microarrays followed by real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) to compare expressions of apoptosis-related genes in the cerebral wall of 18-day-old (E18) fetuses from cocaine-treated (20 mg/kg cocaine, s.c., b.i.d., E8th-E18th) and drug-naive (saline, s.c.) mice. Out of approximately 400 relevant genes in the arrays, 53 showed alterations in expression in cocaine-exposed fetuses. Upregulation was observed in 35 proapoptotic and 8 antiapoptotic genes; 4 proapoptotic and 6 antiapoptotic genes were down-regulated. The affected genes encode a wide range of apoptosis-related proteins, including death receptors (NTF-R1, NTF-R2, DR3, DR5, LTbeta-R, GITR, P57 TR-1) and their adaptor and regulatory proteins (MASGE-D1, TRAF-2, SIVA, MET, FLIP, FAIM, IAP1, ATFA), members of transcription regulatory pathways (JNK, NF-kappaB, P53), members of BCL-2 family of proteins (BID, BAD, BAX, BIK, NIP21, NIP3, NIX, BCL-2), DNA damage sensor (PARP-1), caspases and their substrates and regulatory proteins (caspases 8, 4, 9, and 3, ACINUS, CIDE-A, CIDE-B, GAS2), mitochondrially released factors (cytochrome c, AIF, PRG3), specific endoplasmic reticulum- and oxidative stress-associated factors (BACH2, ABL1, ALG2, CHOP), members of cell survival AKT and HSP70 pathways (PIK3GA, PTEN, HSP70, BAG1, BAG2), and others. This suggests that cocaine affects survival of developing cerebral cells via multiple apoptosis-regulating mechanisms.
...
PMID:Cocaine-induced changes in the expression of apoptosis-related genes in the fetal mouse cerebral wall. 1568 Nov 17

Interleukin-1 (IL-1) is a potent, proinflammatory cytokine, but local environmental factors in inflamed sites or in sepsis may affect cell metabolism and energetics, including the amplitude and duration of IL-1-induced signals, thereby leading to loss of tissue homeostasis. Currently, the mechanisms by which disruption of cell energetics affects inflammatory signaling are incompletely understood. Here, we examined the impact of cell energetics and mitochondrial function on the regulation of IL-1-induced Ca2+ signals and ERK activation in human gingival fibroblasts, cells that are important targets for IL-1-induced destruction of extracellular matrix in inflamed connective tissues. In untreated cells, IL-1 induced a prolonged increase of free intracellular calcium, which was required for ERK activation. Inhibition of cellular energetics by selective depolarization of mitochondria blocked Ca2+ uptake and almost completely abolished IL-1-induced cytosolic Ca2+ signals and ERK activation. IL-1 caused rapid Ca2+ release from the endoplasmic reticulum (ER), concomitant with mitochondrial Ca2+ uptake from ER and non-ER stores. Disruption of mitochondrial energetics abrogated IL-1 induced Ca2+ release from the ER but left other vital cellular functions intact. The negative effect of mitochondrial depolarization on ER release was bypassed by BAPTA/AM, indicating that mitochondrial Ca2+ buffering is the key mechanism in regulating ER release. Thus, in gingival fibroblasts, mitochondrial Ca2+ uptake is essential not only for shaping the kinetics and duration, but also the generation of, IL-1-induced Ca2+ signals. Consequently, mitochondria regulate key downstream effectors of IL-1, including MAP kinases.
...
PMID:Mitochondrial function is a critical determinant of IL-1-induced ERK activation. 1572 61

Overexpression of the EGFR is commonly caused by EGFR gene amplification and is sometimes associated with expression of a variant EGFR (de2-7 EGFR or EGFRvIII) bearing an internal deletion in its extracellular domain. mAb 806 is a novel EGFR antibody with significant antitumor activity that recognizes both the de2-7 EGFR and a subset of the wild-type (wt) EGFR when overexpressed, but does not bind the EGFR expressed in normal tissues. Recently, we demonstrated that the mAb 806 epitope is restricted to a short cysteine loop of the EGFR (amino acids 287-302) that is only available for antibody binding in a transitional form of the receptor, which occurs as the receptor changes from its inactive tethered conformation to a dimeric untethered form. The truncation associated with the de2-7 EGFR mutation renders this receptor constitutively untethered, leading to increased binding of mAb 806. We now show that mAb 806 preferentially binds the immature high-mannose wt and de2-7 EGFR precursors normally located in the endoplasmic reticulum, indicating that this form of the wt EGFR is also constitutively untethered. Using the unique specificity of mAb 806, we clearly demonstrated the presence of these high-mannose EGFR precursors on the cell surface. Given that the high-mannose forms of the wt EGFR must be untethered they may contribute to the spontaneous EGFR signaling reported in cells overexpressing the receptor. These precursor forms of the EGFR thus represent novel tumor targets and contribute to the exceptional selectivity of mAb 806 for EGFR when overexpressed in cancer cells. As our observations are likely to apply to other receptors overexpressed in cancer, they suggest a strategy for developing antitumor antibodies even when the target receptor is expressed in normal tissue.
...
PMID:The antitumor monoclonal antibody 806 recognizes a high-mannose form of the EGF receptor that reaches the cell surface when cells over-express the receptor. 1577 76

Inflammatory myofibroblastic tumor (IMT) is a controversial lesion composed of myofibroblasts, accompanied by varying numbers of inflammatory cells. Various pathogenetic factors have been proposed (ie, reactive, infectious, autoimmune, and neoplastic) but the etiology of most IMTs remains unknown. Here we review the literature of oral IMTs, detailing the demographic profile of these rare lesions. Moreover, we present an unusual case of IMT arising from the mandibular alveolar mucosa of an 82-year-old female. Microscopic examination revealed plump spindle cells set in a myxoid vascular stroma admixed with inflammatory cells. Numerous large ganglion cell-like cells were seen, some exhibiting emperipolesis of neutrophils. Ultrastructurally, prominent myofibroblasts with abundant rough endoplasmic reticulum were noted. Tumor cells were immunoreactive for vimentin, smooth muscle actin, and KP1 (CD68), and negative for desmin, S-100, and EBV-LMP. The lesion was excised without margins and the patient has manifested no evidence of disease at an 18-month recall. In an attempt to further delineate the potential neoplastic nature of this lesion, we assessed the immunohistochemical expression of various markers that have been linked to neoplastic transformation. The recorded positivity for ALK, p53, MDM2, CDK4, pRb, and Ki-67, despite the absence of bcl-2 reactivity, strongly favors the neoplastic origin of the studied tumor.
...
PMID:Oral inflammatory myofibroblastic tumor demonstrating ALK, p53, MDM2, CDK4, pRb, and Ki-67 immunoreactivity in an elderly patient. 1589 59

Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy. In peripheral neuropathy, defects in neurofilament and microtubules have been demonstrated. In this study, we examined the effects of insulin deficiency within the brain in insulin knockout mice (I-/-). The I-/- exhibited hyperphosphorylation of tau, at threonine 231, and neurofilament. In addition, we showed hyperphosphorylation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 beta (GSK-3 beta) at serine 9. Extracellular signal-regulated kinase 1 (ERK 1) showed decrease in phosphorylation, whereas ERK 2 showed no changes. Ultrastructural examination demonstrated swollen mitochondria, endoplasmic reticulum, and Golgi apparatus, and dispersion of the nuclear chromatin. Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches. Thus, lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament, and ultrastructural cellular damage, that over time may induce decrease in cognition and learning disabilities.
...
PMID:The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse. 1603 5

Antibody-drug conjugate therapy entails targeted killing of cancer cells with cytotoxic compounds covalently linked to tumor-specific antibodies and shows promise in the treatment of several human cancers. Current antibody-drug conjugate designs that incorporate a disulfide linker between the antibody and cytotoxic drug are inspired by indirect evidence suggesting that the redox potential within the endosomal system is reducing. It is presumed that antigen-dependent endocytosis leads to disulfide linker reduction and intracellular release of free drug, but direct demonstration of such a mechanism is lacking. To determine whether the disulfide N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP) linker would be reduced during endocytic recycling of the anti-HER2 antibody trastuzumab (Herceptin, Genentech), we synthesized a trastuzumab-SPP-Rhodamine red conjugate and developed a linker cleavage assay by using the self-quenching property of this fluorophore. In breast carcinoma SKBr3 cells, no SPP linker cleavage was observed, as detected by fluorescence dequenching upon internalization. By contrast, the conjugate did display fluorescence dequenching when diverted to the lysosomal pathway by geldanamycin, an effect partly due to proteolytic degradation rather than disulfide reduction. To understand why linker reduction was inefficient, we measured redox potentials of endocytic compartments by expressing a redox-sensitive variant of GFP fused to various endocytic proteins. Unexpectedly, we found that recycling endosomes, late endosomes, and lysosomes are not reducing, but oxidizing and comparable with conditions in the endoplasmic reticulum. These results suggest that intracellular reduction is unlikely to account for the potency of disulfide-linked antibody-drug conjugates.
...
PMID:Oxidizing potential of endosomes and lysosomes limits intracellular cleavage of disulfide-based antibody-drug conjugates. 1632 2

Understanding the role of signal transduction in regulating pathways responsible for cell growth, survival and apoptosis is critical for cancer therapy. We developed and characterized a HER2/neu and Fas overexpressing cell line (BNT.888 ACA2) from a salivary gland adenocarcinoma that arose in a HER2/neu transgenic mouse. We evaluated the effects of Iressa on signal transduction networks downstream of the activated HER2 and the impact on proliferation, cell cycle and apoptosis. Iressa treatment diminished phosphorylation of the HER2/neu and EGFR. Phosphorylation of STAT-3 also decreased and mitogenic signaling through the MAPK pathways was greatly reduced. Cyclin D1 levels decreased, and cells were arrested in G0 and failed to enter S-phase because of hypophosphorylation of Rb and to traverse the G2M checkpoint because of degradation of cyclin B1. Cytostasis occurred within 48 hr at 250-500 nM Iressa. Levels of proapoptotic factors (bim and bax) increased and levels of antiapoptotic factors (bcl-2 and bcl-xL) decreased in a dose-dependent manner. Higher doses of Iressa diminished phosphorylation of Akt slightly, but failed to induce apoptosis. Fas antibody was a potent agonist of apoptosis. Pretreatment with Iressa (1 microM, 24 hr) greatly enhanced Fas-mediated apoptosis as determined by Annexin V binding, cleavage of caspase-3 and PARP. Augmentation of apoptosis was associated with increased Fas expression and membrane localization. Iressa pretreatment increased bid activation, cleavage of caspases -3, -9 and -12 and stress signaling via c Jun. These data showing that Iressa induces cytostasis and primes the extrinsic (Fas) and intrinsic (mitochondrial and endoplasmic reticulum) apoptotic pathways should lead to the development of novel therapeutic targets and strategies.
...
PMID:Iressa induces cytostasis and augments Fas-mediated apoptosis in acinic cell adenocarcinoma overexpressing HER2/neu. 1647 Aug 40

Ammonium transport proteins belonging to the Mep/Amt/Rh family are spread throughout all domains of life. A conserved aspartate residue plays a key role in the function of Escherichia coli AmtB. Here, we show that the analogous aspartate residue is critical for the transport function of eukaryotic family members as distant as the yeast transporter/sensor Mep2 and the human RhAG and RhCG proteins. In yeast Mep2, replacement of aspartate(186) with asparagine produced an inactive transporter localized at the cell surface, whilst replacement with alanine was accompanied by stacking of the protein in the endoplasmic reticulum. Introduction of an acidic residue, glutamate, produced a partially active protein. A carboxyl group at position 186 of Mep2 therefore appears mandatory for function. Kinetic analysis shows the Mep2(D186E) variant to be particularly affected at the level of substrate affinity, suggesting an involvement of aspartate(186) in ammonium recognition. Our data also put forward that ammonium recognition and/or transport by Mep2 is required for the sensor role played in the development of pseudohyphal growth. Finally, replacement of the conserved aspartate with asparagine in human RhAG and RhCG proteins resulted in the loss of bi-directional transport function. Hence, this aspartate residue might play a preserved functional role in Mep/Amt/Rh proteins.
...
PMID:Structural involvement in substrate recognition of an essential aspartate residue conserved in Mep/Amt and Rh-type ammonium transporters. 1647 34

BASH/BLNK/SLP-65 is an adaptor protein necessary for the B cell receptor (BCR) signal transduction. Here we report the identification through the yeast two-hybrid system of a novel 26-kDa protein, BASH N-terminus-associated protein 1 (BNAS1), which interacts with the conserved and functionally important N-terminal domain of BASH/BLNK/SLP-65. BNAS1 presumably contains four transmembrane domains and the leucine zipper (LZ) motif, and is expressed ubiquitously. The association of BNAS1 with BASH/BLNK/SLP-65 through its LZ motif in vertebrate cells was demonstrated by immunoprecipitation assay. Confocal microscopy revealed that exogenously expressed BNAS1 is localized to the endoplasmic reticulum (ER) and the nuclear envelope. BASH/BLNK/SLP-65 alone was present diffusely in the cytoplasm, but localized to the same position as BNAS1 when co-expressed with BNAS1. Their co-localization was dependent on the domains containing the LZ motif of both molecules. BCR-signaled transcriptional activation of Elk-1 was suppressed by over-expression of BNAS1 in DT40 chicken B cells, and conversely augmented in the BNAS1-deficient DT40 cells, which was restored by BNAS1 reconstitution. This augmentation of Elk-1 activation in the BNAS1-deficient cells was abolished selectively by Jun N-terminal kinase (JNK) inhibitor, suggesting that BNAS1 regulates Elk-1 activation through JNK. Taken together, these results suggest that BNAS1 interacts with BASH/BLNK/SLP-65 at the ER and/or the outer nuclear membrane and is involved in the regulation of the signal transmission via mitogen-activated protein kinases leading to Elk-1 activation.
...
PMID:The BASH/BLNK/SLP-65-associated protein BNAS1 regulates antigen-receptor signal transmission in B cells. 1648 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---