Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis.
These data suggest that ERK activation plays a key role in lymphatic EC fate specification and that excessive ERK activation is the basis of lymphatic abnormalities seen in Noonan syndrome and related diseases.
SHOC2 is mutated in Noonan syndrome and plays a key role in the activation of the ERK-MAPK pathway, which is upregulated in the majority of human cancers.
PTPN11 mutations cause LEOPARD syndrome (LS) and Noonan syndrome (NS), two disorders that are part of a newly classified family of autosomal dominant syndromes termed "RASopathies," which are caused by germline mutations in components of the RAS/RAF/MEK/ERK mitogen activating protein kinase pathway.
The data demonstrate both necessity and sufficiency of increased ERK activation downstream of Shp2 in mediating abnormal valve development in a NS mouse model.