Sequence space exploration in SHP2: mechanistic insights from disease-associated mutations.

Authors

Anne E van Vlimmeren, Ziyuan Jiang, Devon A Semoy, Neel H Shah

Published in

The Biochemical journal. Volume 483. Issue 11. Pages 2183-2207. Oct 26, 2026.

Abstract

Multi-domain signaling proteins are regulatable switches that mediate signal transduction with high fidelity and selectivity in response to diverse cues. These proteins often harbor disease-associated mutations that disrupt their regulatory properties or interaction specificity to drive pathogenic signaling. Mapping sequence-structure-function relationships in multi-domain signaling proteins is critical to understanding signaling pathways in both healthy and disease states. The protein tyrosine phosphatase SHP2 is a multi-domain protein that can serve as a model system to dissect the molecular basis of signal transduction: SHP2 combines catalytic activity with several binding sites and domains, integrates a variety of inputs, yields a diverse array of potential downstream outcomes, and has extensive interdomain interactions that regulate both its catalytic activity and scaffolding properties. Moreover, numerous mutations have been identified in SHP2 in a variety of human diseases. In the present review, we discuss the myriad ways in which disease-associated mutations perturb SHP2 structure and function. An emerging theme is that pathogenic signaling and disease type are not exclusively determined by mutation-dependent changes in catalytic activity. Rather, SHP2 pathogenicity is driven by changes to its conformational ensemble, which can perturb both catalytic activity and protein-protein interactions. However, these two functional attributes are sometimes differentially affected by mutations, which gives rise to a large diversity of pathogenic outcomes. At the end of the present review, we discuss several open questions and future research directions for understanding SHP2 and multi-domain signaling proteins more broadly.

PMID:
42929068
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.

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