PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice

Jeroen Paardekooper Overman, Jae-Sung Yi, Monica Bonetti, Matthew Soulsby, Christian Preisinger, Matthew P Stokes, Li Hui, Jeffrey C Silva, John Overvoorde, Piero Giansanti, Albert J R Heck, Maria I Kontaridis, Jeroen den Hertog, Anton M Bennett

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review


Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify "protein zero-related" (PZR), a transmembrane glycoprotein that interfaces with the extracellular matrix to promote cell migration, as a major hyper-tyrosyl-phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hyper-tyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as an NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.

Originele taal-2Engels
Pagina's (van-tot)2874-89
Aantal pagina's16
TijdschriftMolecular and Cellular Biology
Nummer van het tijdschrift15
StatusGepubliceerd - aug 2014


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