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https://doi.org/10.1038/s41698-023-00486-6
Title: | SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition | Authors: | 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 |
Keywords: | Science & Technology Life Sciences & Biomedicine Oncology UBIQUITIN LIGASE RECEPTOR RESISTANCE SMAD7 TARGETS EMT |
Issue Date: | 15-Dec-2023 | Publisher: | NATURE PORTFOLIO | 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 | 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. | Source Title: | NPJ PRECISION ONCOLOGY | URI: | https://scholarbank.nus.edu.sg/handle/10635/248467 | ISSN: | 2397-768X | DOI: | 10.1038/s41698-023-00486-6 |
Appears in Collections: | Staff Publications Elements |
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