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Receptor Protein Tyrosine Phosphatases, cell-cell adhesion and signal transduction: We are studying the role of receptor protein tyrosine phosphatases (RPTPs) in signals transduced upon cell-cell contact. Some RPTPs such as PTPµ have cell adhesion molecule-like extracellular segments and are involved in adhesion-dependent signaling. PTPµ mediates adhesion by binding homophilically, i.e., PTPµ on the surface of one cell binds to PTPµ on an apposing cell. Interestingly, we found that PTPµ associates with another family of cell adhesion molecules called cadherins. Cadherins are adhesion molecules that play a role in cytoskeletal organization and cell junction formation. We are investigating the role of RPTPs and tyrosine phosphorylation in assembly and signal transduction at sites of cell-cell adhesion.
RPTPs and cancer: We are investigating the role of RPTPs in cell growth and malignancy in cancer. Protein tyrosine kinases can cause uncontrolled cell growth by disrupting the balance of cellular phosphotyrosine levels suggesting that PTPs may play an important role in negative growth regulation or could function as tumor suppressors. In this regard, we have recently found that certain cancer cells have lost PTPµ expression. Therefore, we are determining whether restoration of PTPµ expression in cancer cells results in changes in adhesion, growth, tumorigenicity or metastasis.
RPTPs and development of the nervous system: Cell adhesion is critical to the establishment of proper connections in the nervous system. PTPµ is expressed in the brain and may play a role in neuronal development by sending signals in response to cell adhesion. We demonstrated that PTPµ promotes neurite outgrowth from chick retinal ganglion cells and is found in a complex with N-cadherin in retina. PTPµ is permissive to nasal retinal ganglion cells (movie #1) and is repulsive to temporal retinal ganglion cells (movie #2). PTPµ is expressed by retinal ganglion cells whose axons project via the optic nerve to visual centers in the brain. Nasal and temporal neurons project to different areas in the brain. Retinotectal projection or pathfinding of retinal neurons to the brain may be controlled by PTPµ.
Selected Publications
Oblander, S.A., Ensslen-Craig, S.E. and Brady-Kalnay, S.M. E-cadherin promotes retinal ganglion cell neurite outgrowth in a protein tyrosine phosphatase-mu dependent manner. Molecular and Cellular Neuroscience, 34, 481-492. 2007. [PubMed]
Major, D.L. and Brady-Kalnay, S.M. Rho GTPases regulate PTPµ-mediated nasal neurite outgrowth and temporal repulsion of retinal ganglion cell neurons. Molecular and Cellular Neuroscience, 34, 453-467. 2007. [PubMed]
Xie, Y.M., Massa, S.M., Ensslen-Craig, S.E., Major, D.L., Yang, T., Tisi, M., Derevyanny, V., Runge, W., Mehta, B.P., Brady-Kalnay, S.M. and Longo, F.M. PTP wedge domain peptides: a novel approach for inhibition of PTP function and augmentation of PTK function. J. Biological Chemistry, 281, 16482-16492. 2006. [PubMed]
Phillips-Mason, P.J., Gates, T.J., Sacks, D.B. and Brady-Kalnay, S.M. The Receptor Protein Tyrosine Phosphatase PTPµ Interacts with IQGAP1. J. Biological Chemistry, 281, 4903-4910. 2006. [PubMed]
Ensslen-Craig, S.E. and Brady-Kalnay, S.M. PTPµ expression and catalytic activity are required for PTPµ-mediated neurite outgrowth and repulsion. Molecular and Cellular Neuroscience, 28, 177-188. 2005. [PubMed]
Ensslen-Craig, S.E. and Brady-Kalnay, S.M. Receptor protein tyrosine phosphatases regulate neural development and axon guidance. Developmental Biology, 275, 12-22. 2004. [PubMed]
Jain, A., Brady-Kalnay, S.M. and Bellamkonda, R. Modulation of Rho GTPase activity alleviates CSPG-dependent inhibition of neurite extension. Journal of Neuroscience Research, 77, 299-307. 2004. [PubMed]
Ensslen, S.E. and Brady-Kalnay, S.M. PTPµ expression levels and signaling via PKC delta are instructive for retinal ganglion cell guidance in vitro. Molecular and Cellular Neuroscience, 25, 558-571. 2004. [PubMed]
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