Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia

Wenjun Zhang, Rebecca Chan, Hanying Chen, Zhenyun Yang, Yantao He, Xian Zhang, Yong Luo, Fuqing Yin, Akira Moh, Lucy C. Miller, R. Payne, Zhong-Yin Zhang, Xin Yuan Fu, Weinian Shou

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)22353-22363
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number33
DOIs
StatePublished - Aug 14 2009

Fingerprint

Juvenile Myelomonocytic Leukemia
Noonan Syndrome
Bearings (structural)
Cells
Defects
Protein Tyrosine Phosphatases
Granulocyte-Macrophage Colony-Stimulating Factor
Ablation
Mutation
Bone
Blood
Chemical activation
Tissue
Multiple Birth Offspring
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Pulmonary Valve Stenosis
Bone Marrow Cells
Hyperplasia
Blood Cells
Hypersensitivity

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. / Zhang, Wenjun; Chan, Rebecca; Chen, Hanying; Yang, Zhenyun; He, Yantao; Zhang, Xian; Luo, Yong; Yin, Fuqing; Moh, Akira; Miller, Lucy C.; Payne, R.; Zhang, Zhong-Yin; Fu, Xin Yuan; Shou, Weinian.

In: Journal of Biological Chemistry, Vol. 284, No. 33, 14.08.2009, p. 22353-22363.

Research output: Contribution to journalArticle

Zhang, Wenjun ; Chan, Rebecca ; Chen, Hanying ; Yang, Zhenyun ; He, Yantao ; Zhang, Xian ; Luo, Yong ; Yin, Fuqing ; Moh, Akira ; Miller, Lucy C. ; Payne, R. ; Zhang, Zhong-Yin ; Fu, Xin Yuan ; Shou, Weinian. / Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 33. pp. 22353-22363.
@article{35a728dc716845ae8cad5fee0a52e8d9,
title = "Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia",
abstract = "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.",
author = "Wenjun Zhang and Rebecca Chan and Hanying Chen and Zhenyun Yang and Yantao He and Xian Zhang and Yong Luo and Fuqing Yin and Akira Moh and Miller, {Lucy C.} and R. Payne and Zhong-Yin Zhang and Fu, {Xin Yuan} and Weinian Shou",
year = "2009",
month = "8",
day = "14",
doi = "10.1074/jbc.M109.020495",
language = "English",
volume = "284",
pages = "22353--22363",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "33",

}

TY - JOUR

T1 - Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia

AU - Zhang, Wenjun

AU - Chan, Rebecca

AU - Chen, Hanying

AU - Yang, Zhenyun

AU - He, Yantao

AU - Zhang, Xian

AU - Luo, Yong

AU - Yin, Fuqing

AU - Moh, Akira

AU - Miller, Lucy C.

AU - Payne, R.

AU - Zhang, Zhong-Yin

AU - Fu, Xin Yuan

AU - Shou, Weinian

PY - 2009/8/14

Y1 - 2009/8/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=69249118196&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69249118196&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.020495

DO - 10.1074/jbc.M109.020495

M3 - Article

C2 - 19509418

AN - SCOPUS:69249118196

VL - 284

SP - 22353

EP - 22363

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 33

ER -