Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPα and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation

Abstract

Noonan syndrome (NS) is an autosomal dominant disorder that is associated with multiple developmental abnormalities. Activated mutations of the protein-tyrosine phosphatase, SHP-2/PTPN11, have been reported in ∼50% of NS cases. Despite being activated, NS-associated SHP-2 mutants require plasma membrane proximity to evoke disease-associated signaling. Here we show that NS-associated SHP-2 mutants induce hypertyrosyl phosphorylation of the transmembrane glycoproteins, SIRPα (signal-regulatory protein α) and PZR (protein zero-related), resulting in their increased association with NS-associated SHP-2 mutants. NS-associated SHP-2 mutants enhanced SIRPα and PZR tyrosyl phosphorylation either by impairing SIRPα dephosphorylation or by promoting PZR tyrosyl phosphorylation. Importantly, during embryogenesis in a mouse model of NS, SIRPα and PZR were hypertyrosyl-phosphorylated and bound increased levels of the NS-associated SHP-2 mutant. SIRPα and PZR have been implicated in extracellular matrix-dependent signaling. Mouse embryonic fibroblasts derived from a mouse model of NS displayed enhanced ERK activation in response to fibronectin plating. Knockdown of SIRPα and PZR in these cells attenuated the enhanced activation of ERK following fibronectin plating. Thus, SIRPα and PZR serve as scaffolds that facilitate plasma membrane recruitment and signaling of NS-associated SHP-2 mutants. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.