Please use this identifier to cite or link to this item:
https://doi.org/10.1038/s41698-023-00486-6
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dc.title | SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition | |
dc.contributor.author | Lai, Xianning | |
dc.contributor.author | Lui, Sarah Kit Leng | |
dc.contributor.author | Lam, Hiu Yan | |
dc.contributor.author | Adachi, Yuta | |
dc.contributor.author | Sim, Wen Jing | |
dc.contributor.author | Vasilevski, Natali | |
dc.contributor.author | Armstrong, Nicola J | |
dc.contributor.author | Bridgeman, Stephanie Claire | |
dc.contributor.author | Main, Nathan Michael | |
dc.contributor.author | Tan, Tuan Zea | |
dc.contributor.author | Tirnitz-Parker, Janina EE | |
dc.contributor.author | Thiery, Jean Paul | |
dc.contributor.author | Ebi, Hiromichi | |
dc.contributor.author | Kumar, Alan Prem | |
dc.contributor.author | Eichhorn, Pieter Johan Adam | |
dc.date.accessioned | 2024-05-20T00:45:41Z | |
dc.date.available | 2024-05-20T00:45:41Z | |
dc.date.issued | 2023-12-15 | |
dc.identifier.citation | Lai, Xianning, Lui, Sarah Kit Leng, Lam, Hiu Yan, Adachi, Yuta, Sim, Wen Jing, Vasilevski, Natali, Armstrong, Nicola J, Bridgeman, Stephanie Claire, Main, Nathan Michael, Tan, Tuan Zea, Tirnitz-Parker, Janina EE, Thiery, Jean Paul, Ebi, Hiromichi, Kumar, Alan Prem, Eichhorn, Pieter Johan Adam (2023-12-15). SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition. NPJ PRECISION ONCOLOGY 7 (1). ScholarBank@NUS Repository. https://doi.org/10.1038/s41698-023-00486-6 | |
dc.identifier.issn | 2397-768X | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/248467 | |
dc.description.abstract | Despite the promising antitumor activity of SHP2 inhibitors in RAS-dependent tumours, overall responses have been limited by their narrow therapeutic window. Like with all MAPK pathway inhibitors, this is likely the result of compensatory pathway activation mechanisms. However, the underlying mechanisms of resistance to SHP2 inhibition remain unknown. The E3 ligase SMURF2 limits TGFβ activity by ubiquitinating and targeting the TGFβ receptor for proteosome degradation. Using a functional RNAi screen targeting all known phosphatases, we identify that the tyrosine phosphatase SHP2 is a critical regulator of TGFβ activity. Specifically, SHP2 dephosphorylates two key residues on SMURF2, resulting in activation of the enzyme. Conversely, SHP2 depletion maintains SMURF2 in an inactive state, resulting in the maintenance of TGFβ activity. Furthermore, we demonstrate that depleting SHP2 has significant implications on TGFβ-mediated migration, senescence, and cell survival. These effects can be overcome through the use of TGFβ-targeted therapies. Consequently, our findings provide a rationale for combining SHP2 and TGFβ inhibitors to enhance tumour responses leading to improved patient outcomes. | |
dc.language.iso | en | |
dc.publisher | NATURE PORTFOLIO | |
dc.source | Elements | |
dc.subject | Science & Technology | |
dc.subject | Life Sciences & Biomedicine | |
dc.subject | Oncology | |
dc.subject | UBIQUITIN LIGASE | |
dc.subject | RECEPTOR | |
dc.subject | RESISTANCE | |
dc.subject | SMAD7 | |
dc.subject | TARGETS | |
dc.subject | EMT | |
dc.type | Article | |
dc.date.updated | 2024-05-18T02:22:08Z | |
dc.contributor.department | CANCER SCIENCE INSTITUTE OF SINGAPORE | |
dc.contributor.department | BIOMED INST FOR GLOBAL HEALTH RES & TECH | |
dc.contributor.department | BIOCHEMISTRY | |
dc.description.doi | 10.1038/s41698-023-00486-6 | |
dc.description.sourcetitle | NPJ PRECISION ONCOLOGY | |
dc.description.volume | 7 | |
dc.description.issue | 1 | |
dc.published.state | Published | |
Appears in Collections: | Staff Publications Elements |
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SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition.pdf | 6.3 MB | Adobe PDF | OPEN | None | View/Download |
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