Developmental cell, 2010-05, Vol.18 (5), p.750-762
2010
Details
- Autor(en) / Beteiligte
- Titel
- Phosphatase-Dependent and -Independent Functions of Shp2 in Neural Crest Cells Underlie LEOPARD Syndrome Pathogenesis
- Ist Teil von
- Developmental cell, 2010-05, Vol.18 (5), p.750-762
- Ort / Verlag
- Cambridge, MA: Elsevier Inc
- Erscheinungsjahr
- 2010
- Link zum Volltext
- Quelle
- ScienceDirect Journals (5 years ago - present)
- Beschreibungen/Notizen
- 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. ► SHP2 has phosphatase-dependent and -independent functions in neural crest cells ► SHP2, via ERK activation, represses SOX10 and FOXD3 to promote differentiation ► The SH2 domains of Shp2 block p53-induced apoptosis in zebrafish and human cells ► The multiple roles of Shp2 can explain the unique features of LEOPARD syndrome
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1534-5807eISSN: 1878-1551DOI: 10.1016/j.devcel.2010.03.009Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3035154
- Format
- –
- Schlagworte
- Animals, Biological and medical sciences, Cell Differentiation, Cell differentiation, maturation, development, hematopoiesis, Cell Division, Cell Movement, Cell physiology, Cell Survival, Complex syndromes, Danio rerio, DEVBIO, Fundamental and applied biological sciences. Psychology, Gastrula - physiology, Germ-Line Mutation, Humans, HUMDISEASE, LEOPARD Syndrome - genetics, LEOPARD Syndrome - pathology, Medical genetics, Medical sciences, Molecular and cellular biology, Neural Crest - physiology, Neural Tube - physiology, Noonan Syndrome - genetics, Noonan Syndrome - pathology, Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 1 - physiology, Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics, RNA, Messenger - genetics, Transcription, Genetic, Zebrafish - embryology, Zebrafish - genetics