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Updated: Aug 17, 2026
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes
Heike Keilhack1, Frank S David, Malcolm McGregor
1Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Abstract:
Mutations in the Src homology 2 (SH2)-containing protein-tyrosine phosphatase Shp2 (PTPN11) underlie half of the cases of the autosomal dominant genetic disorder Noonan syndrome, and somatic Shp2 mutations are found in several hematologic and solid malignancies. Earlier studies of small numbers of mutants suggested that disease-associated mutations cause constitutive (SH2 binding-independent) activation and that cancer-associated mutants are more active than those associated with Noonan syndrome. We have characterized a larger panel of Shp2 mutants and find that this "activity-centric" model cannot explain the behaviors of all pathogenic Shp2 mutations. Instead, enzymatic, structural, and mathematical modeling analyses show that these mutants can affect basal activation, SH2 domain-phosphopeptide affinity, and/or substrate specificity to varying degrees. Furthermore, there is no absolute correlation between the mutants' extents of basal activation and the diseases they induce. We propose that activated mutants of Shp2 modulate signaling from specific stimuli to a subset of effectors and provide a theoretical framework for understanding the complex relationship between Shp2 activation, intracellular signaling, and pathology.
Insights
Pathogenic mutations in Shp2 phosphatase (PTPN11) cause Noonan syndrome and cancers. This study reveals that disease-causing Shp2 mutants exhibit diverse effects on enzyme activity, challenging previous models and offering a new framework for understanding Shp2-related pathologies.
Area of Science:
- Molecular Biology
- Biochemistry
- Genetics
Background:
- Mutations in the protein-tyrosine phosphatase Shp2 (PTPN11) are implicated in Noonan syndrome and various cancers.
- Previous research suggested disease-associated Shp2 mutations lead to constitutive activation, with cancer mutants being more active than those linked to Noonan syndrome.
Purpose of the Study:
- To investigate the functional consequences of a larger panel of Shp2 mutants.
- To re-evaluate the 'activity-centric' model of Shp2 pathogenesis.
- To establish a theoretical framework for understanding the link between Shp2 activation and disease.
Main Methods:
- Enzymatic assays to measure phosphatase activity.
- Structural analyses of Shp2 mutants.
- Mathematical modeling to analyze Shp2 function.
- Characterization of a diverse set of Shp2 mutants.
Main Results:
- The 'activity-centric' model does not fully explain all pathogenic Shp2 mutations.
- Mutants differentially impact basal activation, SH2 domain binding affinity, and substrate specificity.
- No direct correlation exists between the degree of basal activation and the specific disease induced.
- Activated Shp2 mutants selectively modulate specific signaling pathways.
Conclusions:
- Shp2 pathogenesis is more complex than previously thought, involving diverse mechanisms beyond simple constitutive activation.
- Understanding the nuanced effects of Shp2 mutations on signaling is crucial for comprehending associated diseases.
- A new theoretical framework is proposed to link Shp2 activation states to intracellular signaling and pathology.
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