2025-09-15 イェール大学
<関連情報>
- https://medicine.yale.edu/news-article/uncovering-drivers-ofand-treatment-fornoonan-syndrome-heart-defects/
- https://www.pnas.org/doi/10.1073/pnas.2503631122
NSML関連RAS病変におけるSHP2遺伝子変異はPZR–IRX転写因子シグナル伝達軸を破壊する SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis
Sravan Perla, Amy L. Stiegler, Jae-Sung Yi, +6 , and Anton M. Bennett
Proceedings of the National Academy of Sciences Published:August 25, 2025
DOI:https://doi.org/10.1073/pnas.2503631122
Significance
Mutations in the protein tyrosine phosphatase SHP2 that cause Noonan syndrome with multiple lentigines (NSML) result in the development of RASopathy-associated hypertrophic cardiomyopathy (HCM). This study shows that in the heart, when SHP2 interacts in its mutated form with the protein-zero related (PZR) protein, it allows c-Src to bind, causing irregular signaling that affects the Iroquious (IRX) homeobox transcription factors. IRX proteins control BMP10 secretion in the heart, and its dysfunction through aberrant NSML-mediated c-Src activity leads to cardiomyopathy. Significantly, an inhibitor of c-Src restores normal BMP10 expression in NSML mice, suggesting potential therapeutics for the treatment of NSML-associated cardiomyopathy. This finding provides an explanation for how NSML-associated SHP2 genetic variants promote postnatal heart growth in a catalytically independent manner.
Abstract
Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder caused by mutations in PTPN11 (protein tyrosine phosphatase nonreceptor type 11) which encodes for the protein tyrosine phosphatase, SHP2. Approximately 85% of NSML patients develop hypertrophic cardiomyopathy (HCM). Here, we show that SHP2 is recruited to tyrosyl phosphorylated protein-zero related (PZR) in NSML mice. This recruitment is required for the Iroquois homeobox (IRX) transcription factors 3 and 5 to suppress BMP10 which negatively regulates postnatal cardiac growth. The protein expression of IRX3 and IRX5 was elevated in hypertrophied NSML hearts. IRX3 and IRX5 upregulation was rescued in NSML mice harboring a knock-in mutation of PZR that fails to become tyrosyl phosphorylated and recruit SHP2. NSML mice treated with low-dose dasatinib also exhibited normalized IRX3 and IRX5 expression levels. Consistent with this, BMP10 expression levels were reduced in NSML mice and rescued in PZR tyrosyl phosphorylation-deficient and low-dose dasatinib-treated NSML mice. A crystal structure of the tandem SH2 domains of SHP2 bound to tyrosyl phosphorylated PZR reveals that recruitment constrains the open SHP2 conformation to facilitate cellular-Src (c-Src) binding. Disruption of c-Src binding to SHP2 abolished IRX activation and failure to suppress BMP10. Hence, NSML-associated SHP2 genetic variants disrupt IRX transcription factor signaling to BMP10, implicating this axis as a target for RASopathy-associated HCM.
