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.
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.


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.
Kontaridis
Maria I
MI
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, NRB, Room 1036, 77 Ave Louis Pasteur, Boston, MA 02115, USA. mkontari@bidmc.harvard.edu
Yang
Wentian
W
Bence
Kendra K
KK
Cullen
Darragh
D
Wang
Bo
B
Bodyak
Natalya
N
Ke
Qingen
Q
Hinek
Aleksander
A
Kang
Peter M
PM
Liao
Ronglih
R
Neel
Benjamin G
BG
D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D044542:LEOPARD Syndrome / Q000201:enzymology / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009634:Noonan Syndrome / Q000201:enzymology / Q000235:genetics; D009928:Organ Specificity; D010641:Phenotype; D011312:Pressure; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020742:rhoA GTP-Binding Protein
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein