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Updated: Jan 7, 2026
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Understanding Molecular Basis of PTPN11-Related Diseases
Seungha Um1, Tulika Kakati2, Lilia M Iakoucheva2
1National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract:
The PTPN11 gene encodes the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2), a key regulator of cell growth, differentiation, and apoptosis through its modulation of various signaling pathways, including the RAS/MAPK signaling pathway. Missense variants in PTPN11 disrupt SHP2's proper catalytic activity and the regulation of signaling pathways, leading to disorders such as Noonan syndrome (NS), LEOPARD syndrome (LS), or juvenile myelomonocytic leukemia (JMML). These missense variants have molecular disruptions resulting in gains and losses of function at both the molecular and phenotypic levels. Depending on their location within SHP2, missense substitutions disrupt inter-domain regulation or impair phosphatase function, resulting in altered phosphatase activity. In this study, we investigate the molecular basis underlying the differential pathogenicity of PTPN11 missense variants and predict the structural consequences of these variants using MutPred2 and AlphaFold2. We find that LOF and GOF variants display distinct functional mechanisms in sodium and DNA binding, and that NS-associated missense variants identified in fetuses with ultrasound-detected anomalies and familiar cases are more likely to be pathogenic.
Insights
Genetic variants in the PTPN11 gene cause Noonan syndrome and other disorders by altering SHP2 phosphatase activity. This study reveals distinct functional mechanisms for loss-of-function and gain-of-function variants, identifying pathogenic variants linked to fetal anomalies.
Area of Science:
- Genetics and Molecular Biology
- Biochemistry
- Medical Genetics
Background:
- The PTPN11 gene encodes SHP2 phosphatase, a crucial regulator of cellular processes via signaling pathways like RAS/MAPK.
- Missense variants in PTPN11 are linked to developmental disorders including Noonan syndrome (NS), LEOPARD syndrome (LS), and juvenile myelomonocytic leukemia (JMML).
- These variants can result in altered SHP2 catalytic activity, leading to both loss-of-function (LOF) and gain-of-function (GOF) molecular and phenotypic effects.
Purpose of the Study:
- To elucidate the molecular mechanisms differentiating the pathogenicity of PTPN11 missense variants.
- To predict the structural impacts of PTPN11 variants using computational tools.
- To correlate variant characteristics with clinical outcomes, particularly in NS.
Main Methods:
- Utilized MutPred2 and AlphaFold2 for predicting structural consequences of PTPN11 missense variants.
- Analyzed functional mechanisms, including sodium and DNA binding, for LOF and GOF variants.
- Correlated variant pathogenicity with clinical data from fetuses with ultrasound anomalies and familial cases.
Main Results:
- Identified distinct functional mechanisms for LOF and GOF PTPN11 variants concerning sodium and DNA binding.
- Predicted structural consequences of missense substitutions impacting SHP2 inter-domain regulation and phosphatase activity.
- Found that NS-associated variants in fetuses with ultrasound anomalies and familial cases are more frequently pathogenic.
Conclusions:
- PTPN11 missense variants exhibit diverse pathogenicity based on their impact on SHP2 function and structure.
- Computational prediction tools aid in understanding the molecular basis of variant effects.
- Early identification of pathogenic PTPN11 variants, especially in at-risk fetal populations, is crucial for diagnosis and management of associated syndromes.
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