Receptor protein tyrosine phosphatases (RPTPs) play critical signaling regulatory roles in development, health, and disease progression. Despite the clear importance of RPTPs in signal transduction, very little is known about the structure-function relationships that underpin the regulation of their activity. The reported ability of RPTP homodimerization to antagonize their catalytic activity, however, presents potential opportunities to develop strategies to promote RPTP activity against their oncogenic receptor tyrosine kinase (RTK) substrates. We recently showed, using PTPRJ/EGFR as a model RPTP/RTK pair, that: (i) homodimerization of PTPRJ (also known as DEP1) is regulated by transmembrane domain interactions, and (ii) disrupting these interactions can antagonize PTPRJ homodimerization, reduce substrate EGFR phosphorylation, and antagonize EGFR-driven cell phenotypes. Here, we propose to build upon these new insights along three thematically interconnected, but non-overlapping, specific aims, with the ultimate goals of: (1) demonstrating that RPTP TM domain interactions are essential in regulating their activity and substrate access, and (2) developing a new therapeutic approach to promote RPTP activity against their oncogenic RTK substrates. In our first aim, we will determine the molecular determinants regulating the heterodimerization of PTPRJ with EGFR. These studies will be complemented by extending them to understand how PTPRJ TM domain mutants affect receptor trafficking and ultimate cell outcomes. In the second aim, we will design and select peptides capable of binding to PTPRJ TM domains and test their ability to disrupt PTPRJ homodimerization, promote PTPRJ activity against EGFR and other substrate RTKs, and selectively target human tumor xenografts in mice. In the third aim, we will identify other candidate RTK substrates whose regulation by PTPRJ depends upon TM domain-mediated heterodimerization, and determine how different cellular contexts predict the cell signaling and phenotype outcome of interfering with PTPRJ dimerization through TM domains. To do so, we will implement a systems biology approach based on data-driven computational modeling of phenotypic measurements and global mass spectrometry measurements of protein phosphorylation and expression in a panel of cell lines.
This aim i s motivated by an understanding that all RPTPs have multiple substrates and that variations in expression of those substrates among cells may lead to different outcomes when PTPRJ dimerization is disrupted. Ultimately, the studies proposed here stand to advance both our basic biological understanding of RPTP biology, which is critically needed, and to lead to new methods to target signaling through oncogenic RTKs that may be less susceptible to common mechanisms of acquired resistance to RTK inhibitors.

Public Health Relevance

Despite the critical regulatory roles that receptor protein tyrosine phosphatases (RPTP) play in mammalian signal transduction, the detailed structural basis for the regulation of their catalytic activity is not fully understood, nor are they generally therapeutically targetable. We have recently demonstrated that specific transmembrane domain (TM) interactions and residues are essential in regulating PTPRJ (also known as DEP1) activity and substrate access in cells. Here, we propose to leverage this new knowledge to further advance our basic biological understanding of how RPTP regulate cell signaling pathways in cells, and develop new therapeutic approaches to promote RPTP activity against their oncogenic receptor tyrosine kinase (RTK) substrates.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Barski, Oleg
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Lehigh University
Schools of Arts and Sciences
United States
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