Our goal is to identify novel signaling mechanisms of protein tyrosine phosphatases.
To understand the pathophysiological roles played by protein tyrosine phosphatases and to determine whether these enzymes can be targeted for the treatment of human disease.
Protein tyrosine phosphatases in metabolism
This project focuses on the role of a sub-family of protein tyrosine phosphatases known as mitogen-activated protein kinase (MAPKs) phosphatases (MKPs) in metabolism. We have shown that MKP-1, which specifically dephosphorylates and inactivates the MAPKs in the nucleus is a critical regulator of metabolic homeostasis. How MKP-1, and other MKPs, function in the control of metabolism is being investigated. We are particularly interested in MKP-1's role in the development of liver diseases such as non-alcoholic steatohepatitis which can lead to liver cancer.
Protein tyrosine phosphatases in the RAS pathway
Mutations in the Ras-mitogen-activated protein kinase (MAPK) pathway that cause genetic developmental disorders are referred to as RASopathies. The SH2 domain-containing protein tyrosine phosphatase (PTP) 2 (Shp2) is mutated in nearly 50% of cases that cause Noonan syndrome (NS) an autosomal dominant RASopathy that gives rise to pleiotropic clinical presentations, including congenital heart disease. We are investigating how disease-associated mutations in Shp2 causes congenital heart disease by identifying new targets in this pathway.
Protein tyrosine phosphatases in degenerative diseases and tissue repair
Duchenne's muscular dystrophy is a rare disease that leads to the degeneration of skeletal muscle function. In dystrophic skeletal muscle, mutations in structural proteins render the muscle architecturally unstable resulting in susceptibility to damage, onset of necrosis, inflammation and repair; the chronicity of which culminates in fibrosis. We have discovered that the mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5), is a central mediator of skeletal muscle fibrosis. We are investigating how MKP-5 is involved in muscle fibrosis and repair in dystrophic muscle disease.
Targeting protein tyrosine phosphatases
Protein tyrosine phosphatases represent attractive targets for the treatment of human disease. However, these enzymes are difficult to drug. We are developing novel modes of inhibiting protein tyrosine phosphatases using a combination of structural and chemical biology approaches. If successful, new classes of MKP inhibitors could be developed for the potential treatment of fibrotic tissue disease, cancer and metabolic disease.