title: PZR coordinates Shp2 Noonan and LEOPARD syndrome signaling in zebrafish and mice.
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.
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Paardekooper Overman
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Yi
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Bonetti
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Soulsby
authors.affiliation: Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Preisinger
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Stokes
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Hui
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Silva
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Overvoorde
authors.affiliation: Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, Netherlands.
authors.forename: Piero
authors.initials: P
authors.lastname: Giansanti
authors.affiliation: Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht University, Utrecht, Netherlands.
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.affiliation: Harvard Medical School, Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Kontaridis
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, Netherlands Institute Biology Leiden, Leiden, Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
authors.affiliation: 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.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
mesh_terms: D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D044542:LEOPARD Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D009634:Noonan Syndrome / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11