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168 results on '"Wang, Kehuan"'

3. Enhanced Mechanical Properties of High Temperature Titanium Alloy Components by Fast Gas Forming with In-Die Quenching

Author

Chen, Wentao, Dang, Kexin, Wang, Kehuan, Liu, Gang, Chaari, Fakher, Series Editor, Gherardini, Francesco, Series Editor, Ivanov, Vitalii, Series Editor, Haddar, Mohamed, Series Editor, Cavas-Martínez, Francisco, Editorial Board Member, di Mare, Francesca, Editorial Board Member, Kwon, Young W., Editorial Board Member, Trojanowska, Justyna, Editorial Board Member, Xu, Jinyang, Editorial Board Member, Mocellin, Katia, editor, Bouchard, Pierre-Olivier, editor, Bigot, Régis, editor, and Balan, Tudor, editor

Published
2024
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43. Modulation of PDGF receptors function by posttranslational modifications

Author

Wang, Kehuan

Subjects
autophagy, Cell- och molekylärbiologi, SQSTM1/p62, GABARAP, ubiquitination, DUB, SUMOylation, STAT3, PDGF signaling, SUMO, bafilomycin A1, receptor tyrosine kinase, LC3, cleavage, Cell and Molecular Biology
Abstract

The platelet-derived growth factor receptors (PDGFRs) play important roles in multiple cellular processes including cell survival, cell growth and cell migration. Dysregulation of PDGFRs causes aberrant PDGF signaling, which leads to various diseases. Insights from the research about PDGF/PDGFR signaling have enlightened new opportunities to understand the molecular mechanisms of cancer and other diseases. The goal of this thesis is to further investigate the mechanisms of the modulation of PDGF/PDGFR signaling to identify new ways of controlling aberrant signaling of these RTKs in various diseases, including cancer. Ubiquitination is an important post-translational modification related to protein degradation, receptor internalization, intracellular trafficking, cell proliferation, and other cellular processes. It can be reversed by DUBs, and the overexpression of DUBs is involved in various diseases including cancers. In paper I, we identified two main DUBs working on PDGFRβ, USP17 and USP4. They affected the timing of STAT3 activation and trafficking via different mechanisms, thus fine-tuning its transcriptional activity, which further regulated the proliferative response induced by PDGF-BB. SUMOylation is another post-translational modification that is important for the regulation of protein subcellular localization, protein stability, protein-DNA interactions, protein-protein interactions, genome organization, DNA repair and transcriptional regulation. In paper II, we have identified PDGFRα as a SUMOylation substrate and performed a characterization of the functional role of SUMOylation in PDGFRα signaling and cell proliferation. Proteolytic cleavage of RTKs regulates their downstream signaling pathways by affecting their structure, stability, subcellular localization and interaction with other proteins. In paper III, we have identified that PDGFRβ is cleaved in the region Y579-Y857 upon ligand stimulation by a Ca2+-dependent protease, which is dependent on its internalization. The proteasomal inhibitor bortezomib blocked the internalization, as well as the cleavage of PDGFRβ, and also affected its downstream signaling. Apart from the classic degradation in lysosomes and proteasomes, several RTKs have also been found to undergo autophagy and to be targeted in autophagosomes which further fuse with lysosomes. In liver hepatocytes (LX2) cells, it has been reported that PDGFRα, but not PDGFRβ, undergo selective autophagy. In paper IV, we identified that in certain types of cells, PDGFRβ may be involved in the autophagy pathway, which may affect the synthesis of new PDGFRβ. To conclude, in this study, we investigated how the turnover and signaling of the RTKs PDGFR isoforms α and β are modulated by ubiquitination, SUMOylation, proteolytic cleavage and degradation.

Published
2023

46. Deubiquitinating enzymes USP4 and USP17 finetune the trafficking of PDGFR beta and affect PDGF-BB-induced STAT3 signalling

Author

Sarri, Niki, Wang, Kehuan, Tsioumpekou, Maria, Castillejo-Lopez, Casimiro, Lennartsson, Johan, Heldin, Carl-Henrik, Papadopoulos, Natalia, Sarri, Niki, Wang, Kehuan, Tsioumpekou, Maria, Castillejo-Lopez, Casimiro, Lennartsson, Johan, Heldin, Carl-Henrik, and Papadopoulos, Natalia

Abstract

Interaction of platelet-derived growth factor (PDGF) isoforms with their receptors results in activation and internalization of receptors, with a concomitant activation of downstream signalling pathways. Ubiquitination of PDGFRs serves as a mark to direct the internalization and sorting of the receptors. By overexpressing a panel of deubiquitinating enzymes (DUBs), we found that USP17 and USP4 efficiently deubiquitinate PDGF receptor beta (PDGFR beta) and are able to remove both Lys63 and Lys48-linked polyubiquitin chains from the receptor. Deubiquitination of PDGFR beta did not affect its stability, but regulated the timing of its trafficking, whereby USP17 prolonged the presence of the receptor at the cell surface, while USP4 affected the speed of trafficking towards early endosomes. Induction of each of the DUBs in BJhTERT fibroblasts and U2OS osteosarcoma cells led to prolonged and/or shifted activation of STAT3 in response to PDGF-BB stimulation, which in turn led to increased transcriptional activity of STAT3. Induction of USP17 promoted acute upregulation of the mRNA expression of STAT3-inducible genes STAT3, CSF1, junB and c-myc, while causing long-term changes in the expression of myc and CDKN1A. Deletion of USP17 was lethal to fibroblasts, while deletion of USP4 led to a decreased proliferative response to stimulation by PDGF-BB. Thus, USP17- and USP4-mediated changes in ubiquitination of PDFGR beta lead to dysregulated signalling and transcription downstream of STAT3, resulting in defects in the control of cell proliferation.

Published
2022
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47. Feasibility study of a novel hot stamping process for Ti6Al4V alloy

Author

Kopec Mateusz, Wang Kehuan, Wang Yaoqi, Wang Liliang, and Lin Jianguo

Subjects
titanium, hot stamping, metal forming, Engineering (General). Civil engineering (General), TA1-2040
Abstract

To investigate the feasibility of a novel hot stamping process for the Ti6Al4V titanium alloy using low temperature forming tools, mechanical properties of the material were studied using hot tensile tests at a temperature range of 600 - 900°C with a constant strain rate of 1s-1. Hot stamping tests were carried out to verify the feasibility of this technology and identify the forming window for the material. Results show that when the deformation temperature was lower than 700°C, the amount of elongation was less than 20%, and it also had little change with the temperature. However, when the temperature was higher than 700°C, a good ductility of the material can be achieved. During the forming tests, parts failed at lower temperatures (600°C) due to the limited formability and also failed at higher temperatures (950°C) due to the phase transformation. The post-form hardness firstly decreased with the temperature increasing due to recovery and then increased due to the phase transformation. Qualified parts were formed successfully between temperatures of 750 - 850°C, which indicates that this new technology has a great potential in forming titanium alloys sheet components.

Published
2018
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