title: Phosphoproteomics-mediated identification of Fer kinase as a target of mutant Shp2 in Noonan and LEOPARD syndrome.
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.
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Paardekooper Overman
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Research, Utrecht University, Utrecht, The Netherlands; Netherlands Proteomics Centre, Utrecht, The Netherlands; Proteomics Facility, Interdisciplinary Centre for Clinical Research Aachen, Aachen University, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Preisinger
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Prummel
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Monica
authors.initials: M
authors.lastname: Bonetti
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Research, Utrecht University, Utrecht, The Netherlands; Netherlands Proteomics Centre, Utrecht, The Netherlands.
authors.forename: Piero
authors.initials: P
authors.lastname: Giansanti
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Research, Utrecht University, Utrecht, The Netherlands; Netherlands Proteomics Centre, Utrecht, The Netherlands; Centre for Biomedical Genetics, Utrecht, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Heck
authors.affiliation: Hubrecht Institute-Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands; Institute Biology Leiden, Leiden, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques; D044542:LEOPARD Syndrome / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D009634:Noonan Syndrome / Q000201:enzymology* / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C000588865:protein tyrosine phosphatase, non-receptor type 11, a, zebrafish