Phosphoproteomics-mediated identification of Fer kinase as a target of mutant Shp2 in Noonan and LEOPARD syndrome

PLoS One. 2014 Sep 3;9(9):e106682. doi: 10.1371/journal.pone.0106682. eCollection 2014.

Abstract

Noonan syndrome (NS) and LEOPARD syndrome (LS) cause congenital afflictions such as short stature, hypertelorism and heart defects. More than 50% of NS and almost all of LS cases are caused by activating and inactivating mutations of the phosphatase Shp2, respectively. How these biochemically opposing mutations lead to similar clinical outcomes is not clear. Using zebrafish models of NS and LS and mass spectrometry-based phosphotyrosine proteomics, we identified a down-regulated peptide of Fer kinase in both NS and LS. Further investigation showed a role for Fer during development, where morpholino-based knockdown caused craniofacial defects, heart edema and short stature. During gastrulation, loss of Fer caused convergence and extension defects without affecting cell fate. Moreover, Fer knockdown cooperated with NS and LS, but not wild type Shp2 to induce developmental defects, suggesting a role for Fer in the pathogenesis of both NS and LS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Knockdown Techniques
  • LEOPARD Syndrome / enzymology*
  • LEOPARD Syndrome / genetics
  • Mutation*
  • Noonan Syndrome / enzymology*
  • Noonan Syndrome / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proteomics
  • Zebrafish / genetics
  • Zebrafish / metabolism*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Zebrafish Proteins
  • proto-oncogene protein c-fes-fps
  • Protein-Tyrosine Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • protein tyrosine phosphatase, non-receptor type 11, a, zebrafish

Grants and funding

This work was funded, in part, by a grant to JdH from the Research Council for Earth and Life Sciences (ALW 819.02.021) with financial aid from the Netherlands Organisation for Scientific Research (NWO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.