Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis.
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.
Stewart
Rodney A
RA
Dana-Farber Cancer Institute, Department of Pediatric Oncology, Harvard Medical School, Boston, MA 02115, USA. rodney.stewart@hci.utah.edu
Sanda
Takaomi
T
Widlund
Hans R
HR
Zhu
Shizhen
S
Swanson
Kenneth D
KD
Hurley
Aeron D
AD
Bentires-Alj
Mohamed
M
Fisher
David E
DE
Kontaridis
Maria I
MI
Look
A Thomas
AT
Neel
Benjamin G
BG
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002465:Cell Movement; D002470:Cell Survival; D005775:Gastrula / Q000502:physiology; D018095:Germ-Line Mutation; D006801:Humans; D044542:LEOPARD Syndrome / Q000235:genetics / Q000473:pathology; D009432:Neural Crest / Q000502:physiology; D054259:Neural Tube / Q000502:physiology; D009634:Noonan Syndrome / Q000235:genetics / Q000473:pathology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000502:physiology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
D012333:RNA, Messenger; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11