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PMID: 20493809 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Developmental cell ·Vol. 18 ·No. 5 ·2010-05-18 ·Pages 750-62

Stewart RA, Sanda T, Widlund HR, Zhu S, Swanson KD, Hurley AD, Bentires-Alj M, Fisher DE, Kontaridis MI, Look AT, Neel BG

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.

MeSH Terms
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
Chemicals
RNA, Messenger PTPN1 protein, human Protein Tyrosine Phosphatase, Non-Receptor Type 1 Protein Tyrosine Phosphatase, Non-Receptor Type 11
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Stewart Rodney A
Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA. [email protected]
Sanda Takaomi
Widlund Hans R
Zhu Shizhen
Swanson Kenneth D
Hurley Aeron D
Bentires-Alj Mohamed
Fisher David E
Kontaridis Maria I
Look A Thomas
Neel Benjamin G
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Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1878-1551
DOI
10.1016/j.devcel.2010.03.009
Email
[email protected]
Published
2010-05-18
Pages
750-62
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC3035154
Subset
IM
Grants
NHLBI NIH HHS · R01 HL083271 · United States
NCI NIH HHS · R01 CA104605-04 · United States
NINDS NIH HHS · R00 NS058608 · United States
NCI NIH HHS · R37 CA049152-22 · United States
NHLBI NIH HHS · R01 HL083273 · United States
NCI NIH HHS · R01 CA104605 · United States
NCI NIH HHS · R37 CA049152 · United States
NHLBI NIH HHS · R00 HL088514-04 · United States
NHLBI NIH HHS · R00 HL088514 · United States
NHLBI NIH HHS · R01 HL102368 · United States
NHLBI NIH HHS · R01 HL083273-01A2 · United States
NINDS NIH HHS · R00 NS058608-03 · United States
NIAMS NIH HHS · R01 AR043369 · United States
NCI NIH HHS · R37 CA49152 · United States
External Links
PubMed source DOI: 10.1016/j.devcel.2010.03.009 PMC Full Text View journal details
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