期刊
DEVELOPMENTAL CELL
卷 18, 期 5, 页码 750-762出版社
CELL PRESS
DOI: 10.1016/j.devcel.2010.03.009
关键词
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资金
- NIH/NINDS [R00 NS058608]
- Friends for Life, DFCI
- Children's Leukemia Research Association research
- NIH/NHLBI [R00 HL088514]
- [R01 HL083271]
- [R37 CA49152]
- [R01 CA104605]
The tyrosine phosphatase SHP2 (PTPN11) regulates cellular proliferation, survival, migration, and differentiation during development. Germ line 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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