It has long been appreciated that receptor protein tyrosine phosphatases (RPTPs) play key roles in cell adhesion and cell signaling. However, the lack of information on their extracellular binding partners and on the functional link between cell adhesion and intracellular phosphatase activity is currently a substantial gap in our understanding of how these receptors mediate the extracellular binding and tyrosine dephosphorylation events necessary for the development of neural tissues. Among RPTPs, PTPRZ (RPTP2/PTP6) is expressed predominantly on glial cells and has been associated with multiple binding partners such as tenascin-C in the extracellular matrix and contactin1 on neurons. Interactions between PTPRZ and contactin1 induce neurite outgrowth and reduce phosphotyrosine levels in cells expressing PTPRZ. Interestingly, the interactions between PTPRZ and contactin1 are impaired in the presence of tenascin-C, revealing the presence of an intricate interplay between these proteins and the interactions between neurons and glial cells. However, the structural basis for these interactions remains unclear. Our long-term goal of is to dissect the mechanisms of cell adhesion and cell signaling that underlie the construction of neural networks. The objective of this proposal is to provide a structural basis for the binding of PTPRZ to its binding partners, which is a prerequisite first step towards defining the function of the cell adhesion complexes involving PTPRZ. The rationale for the research proposed here is that structural characterizations of receptor-ligand pairs involving PTPRZ would represent a significant progress towards understanding RPTP-mediated cell adhesion. Our preliminary data demonstrate the feasibility of our structural approach and we propose the following specific aims to fulfill the need for a detailed understanding of the structural aspects of RPTP-mediated cell adhesion: (1) to determine the crystal structure of the complex between PTPRZ and contactin1 to provide a structural basis for the adhesive interactions mediated by these two proteins, (2) to analyze the effect of contactin1 binding on the oligomeric state of PTPRZ and its intracellular phosphatase activity and (3) to establish the mechanism by which tenascin-C interferes with the binding between PTPRZ and CNTN1 by determining the crystal structures of PTPRZ-tenascin-C and contactin1-tenascin-C complexes. Our contribution is significant because we will be able to visualize protein interfaces in cell adhesion complexes involving RPTPs, yielding precious information about ligand-receptor specificity as well as potential conformational changes and/or changes in oligomeric states that occur upon ligand binding. These structural insights will lay the foundations upon which biochemical studies of RPTP function will be built. Overall, these studies will be relevant to the mission of NIH because they will provide a clearer molecular picture of the cell adhesion events that underpin the development and maintenance of the nervous system and ultimately illuminate the relationship between cell adhesion and cell signaling mediated by RPTPs.

Public Health Relevance

The incessant tug of war between tyrosine kinases and tyrosine phosphatases regulates critical signaling events in embryogenesis and adulthood. In this application, we propose to determine the structural basis for the interactions between a receptor protein tyrosine phosphatase called PTPRZ and two of its extracellular binding partners. Completion of these studies will constitute an important step in defining the mechanisms that regulate the levels of phosphotyrosine signaling during the construction of neural networks. This work is relevant to public health because it lays the foundation for a molecular understanding of the adhesive and signaling events that govern the development of the nervous system.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Flicker, Paula F
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University of Missouri Kansas City
Schools of Arts and Sciences
Kansas City
United States
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