Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells

Abstract

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. It is due, in part, to the lack of known natural ligands or selective agonists. In contrast to conventional structure-function relationship for receptor tyrosine kinases (RTKs), the activity of RPTPs has been reported to be suppressed by dimerization, which may prevent their access to their RTK substrates. We report here that: (i) homodimerization of PTPRJ (also known as DEP-1) is regulated by specific transmembrane (TM) residues, and (ii) disrupting these interactions can destabilize full-length PTPRJ homodimerization in cells, reduce the phosphorylation of EGFR (a known substrate) and downstream signaling effectors, antagonize EGFR-driven cell phenotypes, and promote substrate access. We demonstrate these points in human cancer cells using both mutational studies and through the identification of a peptide designed to bind to the PTPRJ TM domain. This peptide is the first example of such allosteric agonist of RPTPs. This study, therefore, provides not only fundamental structure-function insights on how PTPRJ activity is tuned by TM interactions in cells but also opportunities to develop a unique class of agents that could be used as tools to probe RPTPs signaling regulating mechanisms or for therapeutic purposes in cancers driven by RTK signaling.