Negative Regulation of Stat3 by Activating PTPN11 Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia

Zhang, Wenjun; Chan, Rebecca J.; Chen, Hanying; Yang, Zhiyuan; He, Yantao; Zhang, Xian; Luo, Yong; Yin, Fuqing; Moh, Akira; Miller, Lucy; Payne, R. Mark; Zhang, Zhong Yin; Fu, Xin; Shou, Weinian

doi:10.1074/jbc.m109.020495

Cited by 53 publications

(45 citation statements)

References 49 publications

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“…On the other hand, AS was observed frequently in Sos1 EK/EK mice and in older Sos1 +/EK mice. Finally, in addition to activation of Ras and Erk, we found that Rac and Stat3 were also activated in Sos1 EK mice, which was not found in the Ptpn11 models (38)(39)(40)44). It is possible, if not likely, that the common phenotypes observed in Sos1 and Ptpn11 models, such as growth delay, craniofacial features, hematological disorders, and some cardiac defects, were due to the enhanced Erk activation seen in both models, whereas the distinct features in the Sos1 model described above were due to the selective activation of Rac and/or Stat3.…”

Section: Discussionmentioning

confidence: 64%

Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

Chen¹,

Wakimoto²,

Conner³

et al. 2010

J. Clin. Invest.

103

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Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%-15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-offunction mutation. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS.

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Section: Discussionmentioning

confidence: 64%

Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

Chen¹,

Wakimoto²,

Conner³

et al. 2010

J. Clin. Invest.

103

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“…4E). Because STAT3 is a substrate of SHP2 (33, 34), the diminished STAT3 activity was likely caused by enhanced dephosphorylation of STAT3 by hyperactive SHP2 E76K .…”

Section: Resultsmentioning

confidence: 99%

Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

Zheng

Waclaw

et al. 2018

Sci. Signal.

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Catalytically activating mutations in Ptpn11, which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan Syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan Syndrome with Multiple Lentigines (NSML, formerly called LEOPARD Syndrome). Both types of disease mutations are gain-of-function mutations because they induce SHP2 to constitutively adopt an open conformation, yet they have opposing effects on SHP2 catalytic activity. Here, we report that the catalytic activity of SHP2 is required for the pathogenic effects of Ptpn11 gain-of-function disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knock-in of the Ptpn11 activating mutation E76K resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were completely suppressed by the additional mutation C459S, which abolishes catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the Ptpn11 inactivating mutation Y279C were also unaffected. Mechanistically, the Ptpn11E76K mutation induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcriptional activator STAT3. Whereas STAT3 activity was reduced in Ptpn11E76K/+ cells, the activities of the kinases ERK and AKT were enhanced, and neural cell–specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic–dependent role of Ptpn11 gain-of-function disease mutations in the pathogenesis of hydrocephalus.

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“…We analyzed the activity of Stat3, one of the known substrates of Shp2 phosphatase (37,38) that has been shown to play an essential role in the mitochondria (39). We found that phosphorylation levels of tyrosine 705 of Stat3, the target of Shp2 enzymatic activity, were substantially decreased in the cytosol and mitochondria of Ptpn11 E76K/ϩ cells (Fig.…”

Section: Lytic Capacity In Ptpn11mentioning

confidence: 99%

Induction of a Tumor-associated Activating Mutation in Protein Tyrosine Phosphatase Ptpn11 (Shp2) Enhances Mitochondrial Metabolism, Leading to Oxidative Stress and Senescence

Zheng¹,

Li²,

Hsu

et al. 2013

Journal of Biological Chemistry

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Background:The pathogenic effects of tumor-associated activating mutations of Ptpn11 have not been well characterized. Results: Ptpn11E76K/ϩ mouse embryonic fibroblasts display increased ROS levels, cellular senescence, and enhanced mitochondrial respiration upon induction of the mutation. Conclusion: Induction of the Ptpn11E76K/ϩ mutation results in oxidative stress by enhancing mitochondrial metabolism. Significance: This study provides novel insights into the initial effects of Ptpn11-activating mutations.

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Negative Regulation of Stat3 by Activating PTPN11 Mutants Contributes to the Pathogenesis of Noonan Syndrome and Juvenile Myelomonocytic Leukemia

Cited by 53 publications

References 49 publications

Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

Induction of a Tumor-associated Activating Mutation in Protein Tyrosine Phosphatase Ptpn11 (Shp2) Enhances Mitochondrial Metabolism, Leading to Oxidative Stress and Senescence

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