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41.
R Herbst R Lammers J Schlessinger A Ullrich 《The Journal of biological chemistry》1991,266(30):19908-19916
The chimeric EK-receptor (EK-R), consisting of the epidermal growth factor receptor (EGF-R) extracellular binding domain and p145c-kit cytoplasmic signal-generating sequences, was fully functional in forming high and low affinity EGF binding sites and in ligand-regulated receptor and substrate phosphorylation activities. Relative to EGF-R, EK-R activation stimulated kit-characteristic phosphorylation of human 293 fibroblast substrate polypeptides. Transient coexpression of EK-R with candidate substrates resulted in ligand-induced phosphorylation of phospholipase C gamma and guanosine triphosphatase-activating polypeptide. The RAF-1 serine/threonine kinase was shown to be associated with activated EK-R, but no tyrosine phosphorylation could be detected. The faithfulness of EK-R substrate phosphorylation specificity was confirmed with stem cell factor-stimulated p145c-kit. 相似文献
42.
Carboxy-terminal truncations of epidermal growth factor (EGF) receptor affect diverse EGF-induced cellular responses. 总被引:2,自引:0,他引:2
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W Li N Hack B Margolis A Ullrich K Skorecki J Schlessinger 《Molecular biology of the cell》1991,2(8):641-649
The binding of epidermal growth factor (EGF) to its receptor induces tyrosine phosphorylation of phospholipase C gamma (PLC gamma), which appears to be necessary for its activation leading to phosphatidyl inositol (PI) hydrolysis. Moreover, EGF-receptor (EGF-R) activation and autophosphorylation results in binding of PLC gamma to the tyrosine phosphorylated carboxy-terminus of the receptor. To gain further insights into the mechanisms and interactions regulating these processes, we have analyzed transfected NIH-3T3 cells expressing two EGF-R carboxy-terminal deletion mutants (CD63 and CD126) with reduced capacity to stimulate PI hydrolysis, Ca2+ rises, and DNA synthesis. In fact, the CD126 mutant lacking 126 carboxy-terminal amino acids, including four tyrosine autophosphorylation sites, was unable to stimulate PI hydrolysis or Ca2+ rise in response to EGF. Surprisingly, EGF binding to the cell lines expressing CD63 or CD126 mutants was followed by similar stimulation of tyrosine phosphorylation of PLC gamma. Our results suggest that although necessary, tyrosine phosphorylation of PLC gamma may not be sufficient for stimulation and PI hydrolysis. It is clear, however, that the carboxy-terminal region of EGF-R is involved in regulation of interactions with cellular targets and therefore plays a crucial role in postreceptor signaling pathways. 相似文献
43.
The effect of fibronectin on myogenesis has been studied in vitro. The addition of purified fibronectin to the myogenic cell line L6 blocks fusion and causes an increase in cell number. The effects of fibronectin could be prevented by the immunoprecipitation of fibronectin from solutions using affinity-purified antifibronectin antibodies. Mild trypsinization of the cells (10 μ/ml trypsin for 20 min) which removes surface fibronectin, causes the rate of fusion to increase when the trypsinization is done just before the cells begin to fuse, day 4 (after the plating of the cells), an inhibition when done on one day earlier, day 3, and has no effect when done after the cells have begun to fuse, day 5. By measuring the binding of rhodamine-labeled antifibronectin antibodies to intact cells, it was found that surface fibronectin increased from day 3 to day 4 and then decreased on day 5. The stimulating effect of trypsin on fusion, therefore, corresponds to the day surface fibronectin reaches a peak. Affinity-purified antifibronectin antibodies were also shown to be capable of enhancing fusion. It is concluded from these results that high levels of fibronectin stimulate events which reduce fusion, whereas the removal of surface fibronectin during critical times either stimulates or reduces fusion. 相似文献
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Nilüfer N. Turan Karni S. Moshal Karim Roder Brett C. Baggett Anatoli Y. Kabakov Saroj Dhakal Ryota Teramoto David Yi-Eng Chiang Mingwang Zhong An Xie Yichun Lu Samuel C. Dudley Jr. Calum A. MacRae Alain Karma Gideon Koren 《The Journal of biological chemistry》2020,295(52):18148
The QT interval is a recording of cardiac electrical activity. Previous genome-wide association studies identified genetic variants that modify the QT interval upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor-α factor), a protein encoding a regulator of endosomal trafficking. However, it was not clear how LITAF might impact cardiac excitation. We investigated the effect of LITAF on the voltage-gated sodium channel Nav1.5, which is critical for cardiac depolarization. We show that overexpressed LITAF resulted in a significant increase in the density of Nav1.5-generated voltage-gated sodium current INa and Nav1.5 surface protein levels in rabbit cardiomyocytes and in HEK cells stably expressing Nav1.5. Proximity ligation assays showed co-localization of endogenous LITAF and Nav1.5 in cardiomyocytes, whereas co-immunoprecipitations confirmed they are in the same complex when overexpressed in HEK cells. In vitro data suggest that LITAF interacts with the ubiquitin ligase NEDD4-2, a regulator of Nav1.5. LITAF overexpression down-regulated NEDD4-2 in cardiomyocytes and HEK cells. In HEK cells, LITAF increased ubiquitination and proteasomal degradation of co-expressed NEDD4-2 and significantly blunted the negative effect of NEDD4-2 on INa. We conclude that LITAF controls cardiac excitability by promoting degradation of NEDD4-2, which is essential for removal of surface Nav1.5. LITAF-knockout zebrafish showed increased variation in and a nonsignificant 15% prolongation of action potential duration. Computer simulations using a rabbit-cardiomyocyte model demonstrated that changes in Ca2+ and Na+ homeostasis are responsible for the surprisingly modest action potential duration shortening. These computational data thus corroborate findings from several genome-wide association studies that associated LITAF with QT interval variation. 相似文献
50.
Practice on a procedural task involves within-session learning and between-session consolidation of learning, with the latter requiring a minimum of about four hours to evolve due to involvement of slower cellular processes. Learning to attend to threats is vital for survival and thus may involve faster memory consolidation than simple procedural learning. Here, we tested whether attention to threat modulates the time-course and magnitude of learning and memory consolidation effects associated with skill practice. All participants (N = 90) practiced in two sessions on a dot-probe task featuring pairs of neutral and angry faces followed by target probes which were to be discriminated as rapidly as possible. In the attend-threat training condition, targets always appeared at the angry face location, forming an association between threat and target location; target location was unrelated to valence in a control training condition. Within each attention training condition, duration of the between-session rest interval was varied to establish the time-course for emergence of consolidation effects. During the first practice session, we observed robust improvement in task performance (online, within-session gains), followed by saturation of learning. Both training conditions exhibited similar overall learning capacities, but performance in the attend-threat condition was characterized by a faster learning rate relative to control. Consistent with the memory consolidation hypothesis, between-session performance gains (delayed gains) were observed only following a rest interval. However, rest intervals of 1 and 24 hours yielded similar delayed gains, suggesting accelerated consolidation processes. Moreover, attend-threat training resulted in greater delayed gains compared to the control condition. Auxiliary analyses revealed that enhanced performance was retained over several months, and that training to attend to neutral faces resulted in effects similar to control. These results provide a novel demonstration of how attention to threat can accelerate and enhance memory consolidation effects associated with skill acquisition. 相似文献