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J. Biol. Chem., Vol. 283, Issue 22, 15328-15338, May 30, 2008

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Noonan Syndrome-associated SHP-2/Ptpn11 Mutants Enhance SIRP and PZR Tyrosyl Phosphorylation and Promote Adhesion-mediated ERK Activation^*

From the Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

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, SIRP (signal-regulatory protein ) and PZR (protein zero-related), resulting in their increased association with NS-associated SHP-2 mutants. NS-associated SHP-2 mutants enhanced SIRP and PZR tyrosyl phosphorylation either by impairing SIRP dephosphorylation or by promoting PZR tyrosyl phosphorylation. Importantly, during embryogenesis in a mouse model of NS, SIRP and PZR were hypertyrosyl-phosphorylated and bound increased levels of the NS-associated SHP-2 mutant. SIRP 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 SIRP and PZR in these cells attenuated the enhanced activation of ERK following fibronectin plating. Thus, SIRP and PZR serve as scaffolds that facilitate plasma membrane recruitment and signaling of NS-associated SHP-2 mutants.

Received for publication, February 21, 2008 , and in revised form, March 27, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01 AR46504 (to A. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar St., New Haven, CT 06520-8066. Tel.: 203-737-2441; Fax: 203-737-2738; E-mail: anton. bennett{at}yale.edu.

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