Signalling mechanisms of the tyrosine phosphatase SHP2 upstream of Ras
type: CreativeWork
description: Normal cell regulation is essential for healthy cell function, including cell growth, differentiation, migration, and apoptosis. Dysregulation of intracellular signalling pathways, including Ras – mitogen activated protein kinase (MAPK), disrupts normal cell functioning and can lead to various disorders, including cancer and developmental pathologies. SHP2 regulates multiple signalling cascades, including its crucial role in the complete activation of RasMAPK in KRas driven cancers. SHP2 is also the most commonly mutated protein in RASopathies such as Noonan syndrome. SHP2 is therefore an important therapeutic target, with allosteric inhibitors ‘locking’ SHP2 in its autoinhibited state currently in clinical trials. However, the efficacy of such allosteric inhibitors is significantly reduced by strongly activating mutations, which account for 50% of SHP2 variants detected in human cancers. Improved understanding of SHP2 function in intracellular signalling is needed to identify novel therapeutic approaches targeting SHP2, without the previously observed toxicity. Despite the well-described structure and mode of SHP2 autoinhibition, its precise signalling mechanisms remain to be elucidated. SHP2 is a cysteine-based non-receptor protein tyrosine phosphatase (PTP). It is susceptible to redox regulation; although canonically it is thought to be inactivated by oxidation, our lab has identified the capacity for specific redox-regulated interactions with PTPs, at least in vitro. To better understand SHP2 signalling, I focused on identifying substrates and potential redox-switchable interactions. Using a combination of protein pull downs, western blots, and mass spectrometry (MS). DLG5, a scaffolding protein, and RASAL2, a putative RasGAP, were identified as novel redox-regulated SHP2 interactors. I have shown that DLG5 is a likely SHP2 substrate, and mapped the interaction between the SHP2 PTP domain and the C-terminus SH3-GUK domains of DLG5 using transiently expressed DLG…
abstract: Normal cell regulation is essential for healthy cell function, including cell growth, differentiation, migration, and apoptosis. Dysregulation of intracellular signalling pathways, including Ras – mitogen activated protein kinase (MAPK), disrupts normal cell functioning and can lead to various disorders, including cancer and developmental pathologies. SHP2 regulates multiple signalling cascades, including its crucial role in the complete activation of RasMAPK in KRas driven cancers. SHP2 is also the most commonly mutated protein in RASopathies such as Noonan syndrome. SHP2 is therefore an important therapeutic target, with allosteric inhibitors ‘locking’ SHP2 in its autoinhibited state currently in clinical trials. However, the efficacy of such allosteric inhibitors is significantly reduced by strongly activating mutations, which account for 50% of SHP2 variants detected in human cancers. Improved understanding of SHP2 function in intracellular signalling is needed to identify novel therapeutic approaches targeting SHP2, without the previously observed toxicity. Despite the well-described structure and mode of SHP2 autoinhibition, its precise signalling mechanisms remain to be elucidated. SHP2 is a cysteine-based non-receptor protein tyrosine phosphatase (PTP). It is susceptible to redox regulation; although canonically it is thought to be inactivated by oxidation, our lab has identified the capacity for specific redox-regulated interactions with PTPs, at least in vitro. To better understand SHP2 signalling, I focused on identifying substrates and potential redox-switchable interactions. Using a combination of protein pull downs, western blots, and mass spectrometry (MS). DLG5, a scaffolding protein, and RASAL2, a putative RasGAP, were identified as novel redox-regulated SHP2 interactors. I have shown that DLG5 is a likely SHP2 substrate, and mapped the interaction between the SHP2 PTP domain and the C-terminus SH3-GUK domains of DLG5 using transiently expressed DLG…
author: Dutkiewicz, Roksana
language: eng
keywords: SHP2, RasMAPK, Ras, phosphatases
license: https://www.repository.cam.ac.uk/bitstreams/0ec80bc9-f300-4ddf-823e-c7d4c5949892/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2025-04-07
date modified: 2026-07-22T22:24:32Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.120838