# Signaling by Shp2 mutants in RASopathies

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $12,557

## Abstract

Abstract/Project Summary
Congenital heart defects (CHDs) are the most common type of birth defect (~1/100 live births) and the major
cause of birth-related deaths. Mutations in the Ras/mitogen-activated protein kinase (MAPK) pathway known
as “RASopathies” that include Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML)
manifest in a variety of clinical problems but most notably, CHDs. NS and NSML patients exhibit a range of
CHD-related anomalies such as pulmonic valve stenosis, hypertrophic cardiomyopathy and atrial septal
defects. Approximately, 50% of NS and 90% of NSML patients have autosomal dominant mutations in
PTPN11, the gene encoding the SH2 domain-containing protein tyrosine phosphatase, Shp2. NS represents
the most common non-chromosomal cause of CHD. Therefore, understanding the mechanisms of NS, and
subsequently NSML, will provide insight into the causation of some forms of CHD. Using an integrated set of
approaches that include phospho proteomics, zebrafish genetics, biochemistry and cell biology we have
identified protein zero-related (PZR), a transmembrane glycoprotein that binds Shp2, as a novel target protein
involved in heart development. PZR was identified to be aberrantly increased in its levels of tyrosyl
phosphorylation in the heart of mouse models of both NS and NSML suggesting that PZR is a common target
of these RASopathies. Therefore, the aims of this application are to 1) define the molecular determinants
governing downstream signaing of PZR and to determine how PZR serves as a common signaling target for
NS and NSML, 2) test the efficacy of low-dose tyrosine kinase inhibitors to disrupt aberrant PZR/Shp2
signaling to ameliorate the development of NS- and NSML-related CHD and 3) generate novel PZR mouse
models to define the contribution of PZR in the development of NS and NSML-related CHD. Collectively, these
results will provide insight into common mechanisms that underlie both NS and NSML-related CHD. Finally,
novel strategies for the potential treatment of NS/NSML-associated CHD will be uncovered.

## Key facts

- **NIH application ID:** 9988735
- **Project number:** 3R01HL134166-02S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Anton M Bennett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $12,557
- **Award type:** 3
- **Project period:** 2020-02-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988735

## Citation

> US National Institutes of Health, RePORTER application 9988735, Signaling by Shp2 mutants in RASopathies (3R01HL134166-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9988735. Licensed CC0.

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