Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways.

Authors: Kontaridis, Maria I  Yang, Wentian  Bence, Kendra K  Cullen, Darragh  Wang, Bo  Bodyak, Natalya  Ke, Qingen  Hinek, Aleksander  Kang, Peter M  Liao, Ronglih  Neel, Benjamin G 
Citation: Kontaridis MI, etal., Circulation. 2008 Mar 18;117(11):1423-35. doi: 10.1161/CIRCULATIONAHA.107.728865. Epub 2008 Mar 3.
Pubmed: (View Article at PubMed) PMID:18316486
DOI: Full-text: DOI:10.1161/CIRCULATIONAHA.107.728865


BACKGROUND: Heart failure is the leading cause of death in the United States. By delineating the pathways that regulate cardiomyocyte function, we can better understand the pathogenesis of cardiac disease. Many cardiomyocyte signaling pathways activate protein tyrosine kinases. However, the role of specific protein tyrosine phosphatases (PTPs) in these pathways is unknown.
METHODS AND RESULTS: Here, we show that mice with muscle-specific deletion of Ptpn11, the gene encoding the SH2 domain-containing PTP Shp2, rapidly develop a compensated dilated cardiomyopathy without an intervening hypertrophic phase, with signs of cardiac dysfunction appearing by the second postnatal month. Shp2-deficient primary cardiomyocytes are defective in extracellular signal-regulated kinase/mitogen-activated protein kinase (Erk/MAPK) activation in response to a variety of soluble agonists and pressure overload but show hyperactivation of the RhoA signaling pathway. Treatment of primary cardiomyocytes with Erk1/2- and RhoA pathway-specific inhibitors suggests that both abnormal Erk/MAPK and RhoA activities contribute to the dilated phenotype of Shp2-deficient hearts.
CONCLUSIONS: Our results identify Shp2 as the first PTP with a critical role in adult cardiac function, indicate that in the absence of Shp2 cardiac hypertrophy does not occur in response to pressure overload, and demonstrate that the cardioprotective role of Shp2 is mediated via control of both the Erk/MAPK and RhoA signaling pathways.

Annotation

Disease Annotations
Objects Annotated

Additional Information

 
CRRD Object Information
CRRD ID: 12743610
Created: 2017-02-09
Species: All species
Last Modified: 2017-02-09
Status: ACTIVE



NHLBI Logo

RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.