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Perry S Brignola Karen Lackey Sue H Kadwell Christine Hoffman Earnest Horne H Luke Carter J Darren Stuart Kevin Blackburn Mary B Moyer Krystal J Alligood Wilson B Knight Edgar R Wood 《The Journal of biological chemistry》2002,277(2):1576-1585
Epidermal growth factor receptor (EGFR), ErbB-2, and ErbB-4 are members of the type 1 receptor tyrosine kinase family. Overexpression of these receptors, especially ErbB-2 and EGFR, has been implicated in multiple forms of cancer. Inhibitors of EGFR tyrosine kinase activity are being evaluated clinically for cancer therapy. The potency and selectivity of these inhibitors may affect the efficacy and toxicity of therapy. Here we describe the expression, purification, and biochemical comparison of EGFR, ErbB-2, and ErbB-4 intracellular domains. Despite their high degree of sequence homology, the three enzymes have significantly different catalytic properties and substrate kinetics. For example, the catalytic activity of ErbB-2 is less stable than that of EGFR. ErbB-2 uses ATP-Mg as a substrate inefficiently compared with EGFR and ErbB-4. The three enzymes have very similar substrate preferences for three optimized peptide substrates, but differences in substrate synergies were observed. We have used the biochemical and kinetic parameters determined from these studies to develop an assay system that accurately measures inhibitor potency and selectivity between the type 1 receptor family. We report that the selectivity profile of molecules in the 4-anilinoquinazoline series can be modified through specific aniline substitutions. Moreover, these compounds have activity in whole cells that reflect the potency and selectivity of target inhibition determined with this assay system. 相似文献
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Paula Coln-Bolea Rocío García-Gmez Sue Shackleton Piero Crespo Xos R. Bustelo Berta Casar 《Molecular biology of the cell》2020,31(25):2768
RHO GTPases are key regulators of the cytoskeletal architecture, which impact a broad range of biological processes in malignant cells including motility, invasion, and metastasis, thereby affecting tumor progression. One of the constraints during cell migration is the diameter of the pores through which cells pass. In this respect, the size and shape of the nucleus pose a major limitation. Therefore, enhanced nuclear plasticity can promote cell migration. Nuclear morphology is determined in part through the cytoskeleton, which connects to the nucleoskeleton through the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Here, we unravel the role of RAC1 as an orchestrator of nuclear morphology in melanoma cells. We demonstrate that activated RAC1 promotes nuclear alterations through its effector PAK1 and the tubulin cytoskeleton, thereby enhancing migration and intravasation of melanoma cells. Disruption of the LINC complex prevented RAC1-induced nuclear alterations and the invasive properties of melanoma cells. Thus, RAC1 induces nuclear morphology alterations through microtubules and the LINC complex to promote an invasive phenotype in melanoma cells. 相似文献
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Exogenous galanin stimulates feeding when injected into forebrain and hindbrain sites, including the third and fourth ventricles (3V and 4V), amygdala, paraventricular nucleus of the hypothalamus (PVN), and nucleus of the solitary tract (NTS). Because the PVN and NTS border the ventricular space, it is possible that feeding stimulated by injection of galanin at these sites may be caused by the transport of galanin through the ventricular system to a remote site of action. The role of ventricular transport of galanin between the 3V and 4V in galanin-induced feeding was examined in this study. Rats were implanted with two guide cannula assemblies: one dorsal to the mesencephalic aqueduct and the other in the 3V or 4V. Feeding in response to 3V or 4V galanin injection was first measured after sham-occlusion of the aqueduct. Subsequently, flow of cerebrospinal fluid between the forebrain and hindbrain ventricles was acutely interrupted by injection of a silicone grease plug into the mesencephalic aqueduct just before assessment of the feeding response to 4V or 3V galanin injection. Aqueduct occlusion did not alter the feeding induced by either 3V or 4V galanin injection, indicating that galanin terminals in both the diencephalon and hindbrain are involved in control of food intake. 相似文献
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A gene encoding the endogenous superantigen Mlsc, which deletes Tcrb-V3+ T cells in the NOD inbred mouse strain, was found to co-segregate with Mtv-3 on chromosome 11. This identifies a fourth gene encoding a deletion ligand for Tcrb-V3+ T cells and extends recently published observations in support of the hypothesis that a number of endogenous superantigens are the products of Mtv proviruses.
Address correspondence and offprint requests to : K. Tomonari. 相似文献
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We examined the effects of peroxide on the sarco(endo)plasmicreticulum Ca2+ (SERCA) pump in pigcoronary artery endothelium and smooth muscle at three organizationallevels: Ca2+ transport inpermeabilized cells, cytosolicCa2+ concentration in intactcells, and contractile function of artery rings. We monitored theATP-dependent, azide-insensitive, oxalate-stimulated 45Ca2+uptake by saponin-permeabilized cultured cells. Low concentrations ofperoxide inhibited the uptake less effectively in endothelium than insmooth muscle whether we added the peroxide directly to theCa2+ uptake solution or treatedintact cells with peroxide and washed them before the permeabilization.An acylphosphate formation assay confirmed the greater resistance ofthe SERCA pump in endothelial cells than in smooth muscle cells.Pretreating smooth muscle cells with 300 µM peroxide inhibited (by 77 ± 2%) the cyclopiazonic acid (CPA)-induced increase in cytosolicCa2+ concentration in aCa2+-free solution, but it did notaffect the endothelial cells. Peroxide pretreatment inhibited theCPA-induced contraction in deendothelialized arteries with a 50%inhibitory concentration of 97 ± 13 µM, but up to 500 µMperoxide did not affect the endothelium-dependent, CPA-inducedrelaxation. Similarly, 500 µM peroxide inhibited the angiotensin-induced contractions in deendothelialized arteries by 93 ± 2%, but it inhibited the bradykinin-induced,endothelium-dependent relaxation by only 40 ± 13%. The greaterresistance of the endothelium to reactive oxygen may be importantduring ischemia-reperfusion or in the postinfection immune response. 相似文献
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