ZFIN ID: ZDB-PUB-140529-6
PZR Coordinates Shp2 Noonan and LEOPARD Syndrome Signaling in Zebrafish and Mice
Paardekooper Overman, J., Yi, J.S., Bonetti, M., Soulsby, M., Preisinger, C., Stokes, M.P., Hui, L., Silva, J.C., Overvoorde, J., Giansanti, P., Heck, A.J., Kontaridis, M.I., den Hertog, J., Bennett, A.M.
Date: 2014
Source: Molecular and cellular biology   34(15): 2874-89 (Journal)
Registered Authors: den Hertog, Jeroen, Overvoorde, John
Keywords: none
MeSH Terms:
  • Animals
  • Female
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins/genetics*
  • Intracellular Signaling Peptides and Proteins/metabolism
  • LEOPARD Syndrome/genetics*
  • LEOPARD Syndrome/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation/genetics
  • NIH 3T3 Cells
  • Noonan Syndrome/genetics*
  • Noonan Syndrome/metabolism
  • Phosphorylation/genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
  • Signal Transduction/genetics*
  • Zebrafish/genetics*
  • Zebrafish/metabolism
PubMed: 24865967 Full text @ Mol. Cell. Biol.
Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding for 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, which interfaces with the extracellular matrix to promote cell migration, as a major hypertyrosyl phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hypertyrosyl 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 a 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.