Research Focus

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.

Selected publications from Dr. Bennett's Bibliography (click for PDF)

Eminaga, S. and Bennett, A.M. (2008) Noonan Syndrome-associated SHP-2/Ptpn11 Mutants Enhance SIRPα and PZR Tyrosyl Phosphorylation and Promote Adhesion-mediated ERK Activation, J. Biol. Chem., 283: 15328-15338.

Ha, C.H., Bennett, A.M. and Jin, Z.G. (2008) A novel role of vascular endothelial cadherin in modulating c-Src activation and downstream signaling of vascular endothelial growth factor., J. Biol. Chem., 283: 7261-7270.

Tiganis, T. and Bennett, A.M. (2007) Protein Tyrosine Phosphatases – The Substrate Perspective, Biochem. J., 402: 1-15.

Zito, C.M., Qin, H., Blenis, J. and Bennett, A.M. (2007) SHP-2 regulates cell growth by controlling the mTOR/S6 Kinase 1 pathway, J. Biol. Chem., 282: 6946-6953.31.

Chi, H., Bennett, A.M. and Flavell, R.A. (2007) MAP kinase phosphatase 1 (MKP-1): a critical regulator of innate immune responses, J. Organ Dysfunction, 3: 72-81.

Wu J.J., Roth, J. R., Anderson E., Hong, E., Lee, M., Choi, C., Neufer, D., Kim, J., Shulman, G. S., Bennett, A.M. (2006) Enhanced MAP Kinase Activity and Resistance to Diet-Induced Obesity in Mice Lacking MAP Kinase Phosphatase-1, Cell Metabolism, 4: 61-73.

Fornaro, M., Burch, P., Yang, W., Kim, J. H., Neel, B.G., and Bennett, A.M. (2006) SHP-2 Activates Signaling of the Nuclear-Factor of Activated T-Cells to Promote Skeletal Muscle Growth, J. Cell Biol., 175: 87-97.

Chi, H., Barry, S., Roth, J. R., Wu, J. J., Jones, E. A., Bennett, A. M., and Flavell, R. A. (2006) Dynamic regulation of pro- and anti-inflammatory cytokines by MKP-1 in innate immune responses, Proc. Natl. Acad. Sci., USA, 103: 2274-2279.

Uhlén, P., Burch, P., Estrada, M., Zito, C. M. I., Ehrlich, B. E., and Bennett, A. M. (2006) Noonan syndrome/Gain-of-function Shp-2/Ptpn11 mutants Enhance Calcium Oscillations and Impair NFAT Signaling, Proc. Natl. Acad. Sci., USA, 103: 2160-2165.

Wu, J.J., Zhang, L., and Bennett, A.M. (2005) The Noncatalytic Amino Terminus of Mitogen-Activated Protein Kinase Phosphatase-1 Directs Nuclear Targeting and Serum Response Element Transcriptional Regulation, Mol. Cell. Biol., 25: 4792-4803.

Wu, J.J., and Bennett, A.M. (2005) Essential Role for Mitogen-Activated Protein (MAP) Kinase Phosphatase-1 in Stress-Responsive MAP Kinase and Cell Survival Signaling. J. Biol. Chem. 280: 16461-16466.

Kolli, S., Zito, C., and Bennett, A.M. (2004) The Major Vault Protein (MVP) is a novel substrate for the tyrosine phosphatase SHP-2 and Scaffold Protein in Epidermal Growth Factor Receptor signaling, J. Biol. Chem., 279: 29374-29385.

Kontaridis, M.I., Eminaga, S., Fornaro, M., Zito, C.I., Sordella, R., Settleman, J., and Bennett, A.M. (2004) SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway, Mol. Cell. Biol., 24: 5340-5352.

Zito, C.M., Kontaridis, MI, Fornaro, M., Feng, G.S. and Bennett, A.M. (2004) SHP-2 Regulates the phosphatidylinositol 3'-kinase/Akt pathway and suppresses capsase 3-mediated apoptosis, J. Cell Physiol, 199: 227-236.

Leite, M.F., Thrower, E.C., Ecevarria, W., Koulen, P., Hirata, K., Bennett, A.M., Ehrlich, B.E. and Nathanson, M.H. (2003) Nuclear and cytosolic calcium are regulated independently, Proc. Natl. Acad. Sci., 100: 2975-2980.

Pusl, T., Wu, J.J., Zimmerman, T.L., Zhang, L., Ehrlich, B.E., Berchtold, M.W., Hoek, J.B., Karpen, S. J., Nathanson, M.H. and Bennett, A.M. (2002) Epidermal growth factor-mediated activation of the ETS-domain transcription factor Elk-1 requires nuclear calcium, J. Biol. Chem., 277: 27517-27527.

Kontaridis, M. I., Liu, X., Zhang, L. and Bennett, A.M. (2002) Role of SHP-2 in FGF Receptor-Mediated Suppression of Myogenesis in C2C12 myoblasts, Mol. Cell Biol., 22: 3875-3891.

Kontaridis, M.I., Liu, X., Zhang, L. and Bennett, A.M. (2001) SHP-2 complex formation with SHP-2 Substrate-1 during C2C12 myogenesis, J. Cell Sci.,114: 2187-2198.

Tiganis, T., Bennett, A. M., Ravichandran, K.S. and Tonks, N.K. (1998) Epidermal Growth Factor Receptor and the adapter protein Shc as specific substrates of T-cell protein tyrosine phosphatase. Mol. Cell Biol., 18: 1622-1634.

Bennett, A. M. and Tonks, N.K. (1997) Regulation of Distinct Stages of Skeletal Muscle Differentiation by Mitogen-Activated Protein Kinases. Science, 278: 1288-1291.