Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia.
Noonan syndrome (NS) is an autosomal dominant congenital disorder characterized by multiple birth defects including heart defects and myeloproliferative disease (MPD). Approximately 50% of NS patients have germline gain-of-function mutations in PTPN11, which encodes the protein-tyrosine phosphatase, Shp2. We provide evidence that conditional ablation of Stat3 in hematopoietic cells and cardiac valvular tissues leads to myeloid progenitor hyperplasia and pulmonary stenosis due to the leaflet thickening, respectively. Consistently, STAT3 activation is significantly compromised in peripheral blood cells from NS patients bearing Shp2-activating mutations. Biochemical and functional analyses demonstrate that activated Shp2 is able to down-regulate Tyr(P)-Stat3 and that constitutively active Stat3 rescues activating mutant Shp2-induced granulocyte-macrophage colony-stimulating factor hypersensitivity in bone marrow cells. Collectively, our work demonstrates that Stat3 is an essential signaling component potentially contributing to the pathogenesis of NS and juvenile myelomonocytic leukemia caused by PTPN11 gain-of-function mutations.
Zhang
Wenjun
W
Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202; Riley Heart Research Center, Indianapolis, Indiana 46202; the Departments of Microbiology and Immunology, Indianapolis, Indiana 46202.
Chan
Rebecca J
RJ
Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202; Section of Neonatology, Department of Pediatrics, Indianapolis, Indiana 46202.
Chen
Hanying
H
Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202.
Yang
Zhenyun
Z
Section of Neonatology, Department of Pediatrics, Indianapolis, Indiana 46202.
He
Yantao
Y
Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Zhang
Xian
X
Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Luo
Yong
Y
Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Yin
Fuqing
F
Section of Neonatology, Department of Pediatrics, Indianapolis, Indiana 46202.
Moh
Akira
A
the Departments of Microbiology and Immunology, Indianapolis, Indiana 46202.
Miller
Lucy C
LC
Section of Neonatology, Department of Pediatrics, Indianapolis, Indiana 46202.
Payne
R Mark
RM
Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202; Riley Heart Research Center, Indianapolis, Indiana 46202.
Zhang
Zhong-Yin
ZY
Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Fu
Xin-Yuan
XY
the Departments of Microbiology and Immunology, Indianapolis, Indiana 46202.
Shou
Weinian
W
Herman B. Wells Center for Pediatric Research, Indianapolis, Indiana 46202; Riley Heart Research Center, Indianapolis, Indiana 46202; Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
D000818:Animals; D005434:Flow Cytometry / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009634:Noonan Syndrome / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D014443:Tyrosine; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse