Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis

Rodney A. Stewart, Takaomi Sanda, Hans R. Widlund, Shizhen Zhu, Kenneth D. Swanson, Aeron D. Hurley, Mohamed Bentires-Alj, David E. Fisher, Maria I. Kontaridis, A. Thomas Look, Benjamin G. Neel

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

The tyrosine phosphatase SHP2 (PTPN11) regulates cellular proliferation, survival, migration, and differentiation during development. Germline mutations in PTPN11 cause Noonan and LEOPARD syndromes, which have overlapping clinical features. Paradoxically, Noonan syndrome mutations increase SHP2 phosphatase activity, while LEOPARD syndrome mutants are catalytically impaired, raising the possibility that SHP2 has phosphatase-independent roles. By comparing shp2-deficient zebrafish embryos with those injected with mRNA encoding LEOPARD syndrome point mutations, we identify a phosphatase- and Erk-dependent role for Shp2 in neural crest specification and migration. We also identify an unexpected phosphatase- and Erk-independent function, mediated through its SH2 domains, which is evolutionarily conserved and prevents p53-mediated apoptosis in the brain and neural crest. Our results indicate that previously enigmatic aspects of LEOPARD syndrome pathogenesis can be explained by the combined effects of loss of Shp2 catalytic function and retention of an SH2 domain-mediated role that is essential for neural crest cell survival.

Original languageEnglish (US)
Pages (from-to)750-762
Number of pages13
JournalDevelopmental Cell
Volume18
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • Devbio
  • Humdisease

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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    Stewart, R. A., Sanda, T., Widlund, H. R., Zhu, S., Swanson, K. D., Hurley, A. D., Bentires-Alj, M., Fisher, D. E., Kontaridis, M. I., Look, A. T., & Neel, B. G. (2010). Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis. Developmental Cell, 18(5), 750-762. https://doi.org/10.1016/j.devcel.2010.03.009