SHP2 clinical phenotype, cancer, or RASopathies, can be predicted by mutant conformational propensities

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• SHP2 phosphatase is crucial for the Ras/MAPK pathway, and its mutations are linked to cancer and RASopathies, a group of neurodevelopmental disorders (NDDs).
• Understanding how the same residue mutations in SHP2 can result in distinct clinical phenotypes (cancer vs. NDDs) is critical for predicting outcomes and developing targeted therapies.

Purpose of the Study:

• To investigate the molecular mechanisms by which SHP2 mutations lead to either cancer or NDDs.
• To determine if mutation outcomes can be predicted based on structural and dynamic properties.
• To propose a therapeutic strategy for SHP2-related disorders.

Main Methods:

• Analysis of mutation data from literature and cancer databases.
• Molecular dynamics simulations of SHP2 mutants.
• Comparison of experimental data and dynamic features of SHP2 mutants.

Main Results:

• Both cancer and Noonan syndrome (NS) mutations favor catalysis-prone conformations of SHP2.
• Cancer-associated mutations accelerate SHP2 activation more than NS mutations at the same loci.
• NS mutations induce weaker SHP2 activation compared to oncogenic mutations, potentially disrupting neural cell differentiation.

Conclusions:

• SHP2 mutation outcomes (cancer vs. NDDs) are influenced by the degree of pathway activation, with stronger activation linked to cancer and moderate activation to NDDs.
• Structural and dynamic analyses provide guidelines for correlating SHP2 mutations with clinical outcomes.
• The findings support a higher cancer risk in RASopathy patients and propose a drug strategy targeting SHP2 variants.