Role of the Protein Tyrosine Phosphatase SHP2 in Human Heart Disease

PTPN11, the gene encoding the protein tyrosine phosphatase SHP2, is a key regulator in processes involving cell growth, differentiation and death. Importantly, mutations in SHP2 have recently been implicated in heart disease, suggesting that the proper regulation of this enzyme is critical to maintaining heart health.  Genetic and biochemical evidence well demonstrate that SHP2 is a positive regulator of intracellular signaling pathways and is required for mitogen activating protein kinase (MAPK) pathway activation.  Indeed, mutations in components of the MAPK pathway are known to contribute to cardiac defects. Previous studies showed that SHP2 knockout mice developed Idiopathic Dilated Cardiomyopathy (IDC) suggesting the importance of SHP2 in heart function.

To assess the role of SHP2 directly in human heart disease, we collected human heart samples from normal, hypertrophic or IDC patients. Interestingly, we found that SHP2 expression is absent in IDC, but not in hypertrophic patient samples.  Moreover, patient samples with hypertrophy, but not IDC, had elevated MAPK activity, suggesting that increased SHP2 activity may be required for upregulation of MAPK signaling and the initial compensatory mechanisms required to prevent heart failure.  SHP2 also forms a hyper-tyrosyl phosphorylated protein complex with a yet unidentified approximately 90kDa protein in the hypertrophic samples, suggesting a possible functional cardioprotective mechanism for SHP2 in preventing transition to end-stage heart failure.  Together these data suggest that SHP2 protein expression may be required to prevent the transition from hypertrophy to end-stage heart failure.