Research ArticleDevelopmental Biology

Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

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Science Signaling  20 Mar 2018:
Vol. 11, Issue 522, eaao1591
DOI: 10.1126/scisignal.aao1591

SHP2 in brain development

The phosphatase SHP2, which is encoded by Ptpn11, is autoinhibited under basal conditions and adopts an open conformation and becomes catalytically active when it binds to signaling partners. Although Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are both associated with gain-of-function mutations that promote the ability of SHP2 to adopt an open conformation, NS-associated mutations activate SHP2, whereas NSML-associated mutations are catalytically inactivating. Zheng et al. found that disease-associated mutations in Ptpn11 caused hydrocephalus in mice by interfering with the normal development of the cells that play an essential role in the transport of cerebrospinal fluid only if the mutation impaired the catalytic activity of SHP2. These findings suggest that both catalytic-dependent and catalytic-independent functions of SHP2 mediate these pathologies and that these differential requirements for catalytic activity in distinct processes may underlie the phenotypic differences between NS and NSML.

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