Stem Cell Center, Yale: Tissue Specific Stem Cells
Yale Core Center for Musculoskeletal Disorders
Protein Tyrosine Phosphatases in Growth and Development.
The net cellular level of tyrosine phosphorylation is regulated by the intrinsic and opposing activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs).
Protein tyrosine phosphorylation mediates numerous fundamental physiological events such as mitogenesis, differentiation, cell movement and apoptosis. Our laboratory is interested in how PTPs participate in the regulation of these cellular processes. In order to decipher how PTPs regulate mammalian cell signaling we use a broad range of approaches from molecular biology to mouse genetic strategies.
SH2 domain-containing PTPs - SHP-2.
SHP-2 is a ubiquitously expressed PTP containing tandem SH2 domains. We have been interested in understanding the role of SHP-2 in skeletal muscle growth and differentiation. We have shown that SHP-2 is critical for growth factor signaling in cultured muscle cells. The activity of SHP-2 also is important for cultured muscle cells to differentiate into multinucleated myotubes. Our research efforts are now focused on understanding the developmental and post-developmental roles of SHP-2 in skeletal muscle using mouse models.
In virtually all cases, the catalytic activity of SHP-2 is required for normal cellular function. However, the substrates that are dephosphorylated by SHP-2 are largely unknown. To identify SHP-2 substrates, we are using proteomic approaches in conjunction with mutants of SHP-2 that selectively bind to its substrate.
Mitogen-activated protein kinase (MAPK) phosphatases - MKP-1.
The activation of the MAPKs is critical for the control of a multitude of biological processes. We are interested in how the MAPKs are regulated by a family of PTPs known as MAPK phosphatases (MKPs) that inactivate the MAPKs by dephosphorylation. We are using mouse genetic approaches to study the role of MKP-1 in vivo.
Integration of PTPs and calcium signaling pathways.
Calcium is an important mediator of intracellular signal transduction. We are interested in how PTPs integrate with calcium signaling pathways in the cytoplasm and nucleus. In order to study the integrated role of PTPs and calcium in the nucleus and cytoplasm, we have developed tools to selectively buffer calcium either in the nucleus or cytoplasm independently. We are employing these targeted calcium buffering tools to determine the compartmental affects of calcium on PTP function.
Extensive Research Description
Cell proliferation, cell differentiation and death are controlled by signaling pathways that are mediated by protein tyrosyl phosphorylation. The net cellular level of protein tyrosyl phosphorylation is regulated by the intrinsic and opposing activities of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Dysregulation of the net level of tyrosyl phosphorylation causes cancer, diabetes, cardiovascular disease and developmental abnormalities.
We focus our studies on how PTPs regulate cell signaling by controlling protein tyrosyl dephosphorylation. We are also exploring how PTPs participate in the pathogenesis of diseases such as obesity and diabetes, cardiovascular disease and developmental abnormalities. These research efforts are being accomplished by using integrated approaches that encompass cell biology, genetics, protein biochemistry, cell imaging and animal models. Our long-term research goals are to uncover the function of PTPs in order to identify whether these enzymes might serve as novel therapeutic targets for the treatment of human diseases.
- Shi, H., Verma, M., Zhang, L. Dong, C., Flavell, R.A., and Bennett, A. M. (2013), Improved Regenerative Myogenesis and Muscular Dystrophy in Mice lacking MKP-5, J. Clin. Invest., 123: 2064-2077.
- Lawan, A., Shi, H., Gratzke, F. and Bennett, A.M. (2013) Diversity of mitogen-activated protein kinase phosphatase-1 functions, Cellular and Molecular Life Sciences (CMLS), 70:223-237.
- Mercan, F., Lee, H., Kolli, S. and Bennett, A. M. (2013) A Novel Role for SHP-2 in Nutrient-Responsive Control of S6 Kinase 1 Signaling, Mol. Cell Biol., 33: 293-306.
- Roth Flach, R.J., Zhang, and Bennett, A.M. (2011) Loss of MAP Kinase Phosphatase-1 protects from hepatic steatosis by repression of CIDEC/Fat-specific protein 27, J. Biol. Chem., 286: 22195-22202.
- Roth, R.J., Le, A., Zhang, L., Samuel, V.T., Shulman, J., and Bennett, A.M., (2009) MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice. J. Clin. Invest., 119:3817-29.