| Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis. | |
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MedLine Citation:
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PMID: 20493809 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Developmental cell Volume: 18 ISSN: 1878-1551 ISO Abbreviation: Dev. Cell Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-24 Completed Date: 2010-07-07 Revised Date: 2012-02-14 |
Medline Journal Info:
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Nlm Unique ID: 101120028 Medline TA: Dev Cell Country: United States |
Other Details:
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Languages: eng Pagination: 750-62 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA. rodney.stewart@hci.utah.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Differentiation Cell Division Cell Movement Cell Survival Gastrula / physiology Germ-Line Mutation* Humans LEOPARD Syndrome / genetics, pathology Neural Crest / physiology Neural Tube / physiology Noonan Syndrome / genetics, pathology Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics, physiology* Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics RNA, Messenger / genetics Transcription, Genetic Zebrafish / embryology, genetics |
| Grant Support | |
ID/Acronym/Agency:
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R00 HL088514/HL/NHLBI NIH HHS; R00 HL088514-04/HL/NHLBI NIH HHS; R00 NS058608/NS/NINDS NIH HHS; R00 NS058608-03/NS/NINDS NIH HHS; R00 NS058608-05/NS/NINDS NIH HHS; R01 AR043369-16/AR/NIAMS NIH HHS; R01 CA104605/CA/NCI NIH HHS; R01 CA104605-04/CA/NCI NIH HHS; R01 HL083271/HL/NHLBI NIH HHS; R01 HL083273-01A2/HL/NHLBI NIH HHS; R01 HL102368-03/HL/NHLBI NIH HHS; R37 CA049152-22/CA/NCI NIH HHS; R37 CA49152/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/RNA, Messenger; EC 3.1.3.48/PTPN1 protein, human; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 1; EC 3.1.3.48/Protein Tyrosine Phosphatase, Non-Receptor Type 11 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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