PZR Coordinates Shp2 Noonan and LEOPARD Syndrome Signaling in Zebrafish and Mice

Abstract

g 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.

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

“…SH2 domain-containing tyrosine phosphatase-2 (SHP2), a ubiquitously expressed nonreceptor PTP containing two Src homology 2 (SH2) domains and one catalytic PTP domain, is encoded by the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene (14). Activating mutations in SHP2 underlie the Noonan syndrome that manifests as congenital heart disease, short stature, and facial dysmorphia (15,16). SHP2 regulates activated tyrosine kinase receptors including PDGFR, by binding to and dephosphorylating them (17,18).…”

Low-dose dasatinib rescues cardiac function in Noonan syndrome

“…*P < 0.05; **P < 0.01; ***P < 0.001. interact directly with the tyrosyl-phosphorylated ITIMs of PZR, resulting in SHP2 activation and initiation of adhesion signaling to ERK1/2 (32). Previously, we demonstrated using a nonbiased differential phosphotyrosyl proteomic screen that PZR is the most hyper-tyrosyl-phosphorylated protein in the hearts of Ptpn11 D61G/+ mice (31). We further showed that the expression of NS-and NSML-associated SHP2 mutants is sufficient to enhance PZR tyrosyl phosphorylation and SHP2 binding (31).…”

“…Previously, we demonstrated using a nonbiased differential phosphotyrosyl proteomic screen that PZR is the most hyper-tyrosyl-phosphorylated protein in the hearts of Ptpn11 D61G/+ mice (31). We further showed that the expression of NS-and NSML-associated SHP2 mutants is sufficient to enhance PZR tyrosyl phosphorylation and SHP2 binding (31). These data suggest that the tyrosine kinase(s) that mediates PZR tyrosyl phosphorylation and subsequently SHP2 binding to PZR may serve as an important driver to promote cardiac dysfunction in both NS and NSML.…”

“…We have previously reported that the transmembrane glycoprotein protein zero-related (PZR) is hyper-tyrosyl phosphorylated during embryogenesis in Ptpn11 D61G/+ NS mutant mice and postdevelopmentally in the hearts of NS and Ptpn11 Y279C/+ NSML mutant mice (31,32). PZR is a transmembrane glycoprotein that is abundant in the heart and binds directly to SHP2 through its immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (33,34).…”

“…PZR is involved in cytoskeleton-mediated signaling to ERK1/2 (32) and, in some cases, cell migration and adhesion (32,(35)(36)(37). Both SHP2-associated NS and NSML mutants induce increased SHP2 complex formation with PZR, resulting in aberrant SHP2 membrane proximity and downstream signaling (31). The identification of a PZR/SHP2 complex as a common dysregulated signaling scaffold in the hearts of both NS and NSML led to the implementation of a pharmacological approach to interfere with this complex.…”