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Mol Cell Biol. 2014 Aug;34(15):2874-89. doi: 10.1128/MCB.00135-14. Epub 2014 May 27.

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

Author information

1
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands.
2
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
3
Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, Netherlands.
4
Cell Signaling Technology, Danvers, Massachusetts, USA.
5
Harvard Medical School, Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
6
Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands Institute Biology Leiden, Leiden, Netherlands.
7
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut, USA anton.bennett@yale.edu.

Abstract

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.

PMID:
24865967
PMCID:
PMC4135572
DOI:
10.1128/MCB.00135-14
[Indexed for MEDLINE]
Free PMC Article

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