About this Digital Document
Cell signaling by receptor protein tyrosine kinases (RTKs) is tightly controlled by the counterbalancing actions of receptor protein tyrosine phosphatases (RPTPs). Due to their role in attenuating the signal‐initiating potency of RTKs, RPTPs have long been viewed as therapeutic targets. However, the development of activators of RPTPs has remained limited. We previously reported that the homodimerization of a representative member of the RPTP family (protein tyrosine phosphatase receptor J or PTPRJ) is regulated by specific transmembrane (TM) residues. Disrupting this interaction by single point mutations promotes PTPRJ access to its RTK substrates (e.g., EGFR and FLT3), reduces RTK's phosphorylation and downstream signaling, and ultimately antagonizes RTK‐driven cell phenotypes. Here, we designed and tested a series of first‐in‐class pH‐responsive TM peptide agonists of PTPRJ that are soluble in aqueous solution but insert as a helical TM domain in lipid membranes when the pH is lowered to match that of the acidic microenvironment of tumors. The most promising peptide reduced EGFR's phosphorylation and inhibited cancer cell EGFR‐driven migration and proliferation, similar to the PTPRJ's TM point mutations. Developing tumor‐selective and TM‐targeting peptide binders of critical RPTPs could afford a potentially transformative approach to studying RPTP's selectivity mechanism without requiring less specific inhibitors and represent a novel class of therapeutics against RTK‐driven cancers.
Full Title
Promoting the activity of a receptor tyrosine phosphatase with a novel <span style="font-variant:small-caps;">pH</span> ‐responsive transmembrane agonist inhibits cancer‐associated phenotypes
Member of
Contributor(s)
Creator: Rizzo, Sophie
Creator: Sikorski, Eden
Creator: Park, Soohyung
Creator: Im, Wonpil
Creator: Vasquez‐Montes, Victor
Creator: Ladokhin, Alexey S.
Creator: Thévenin, Damien
Publisher
Wiley
Date Issued
2023-09-01
Language
English
Type
Genre
Form
electronic document
Media type
Creator role
Faculty
Identifier
Related Item
Protein Science, Volume 32, Number 9, 2023
Rizzo, Sophie, Sikorski, Eden, Park, Soohyung, Im, Wonpil, Vasquez‐Montes, Victor, Ladokhin, Alexey S., & Thévenin, Damien. (2023). Promoting the activity of a receptor tyrosine phosphatase with a novel <span style="font-variant:small-caps;">pH</span> ‐responsive transmembrane agonist inhibits cancer‐associated phenotypes (1–). https://doi.org/10.1002/pro.4742
Rizzo, Sophie, Sikorski, Eden, Park, Soohyung, Im, Wonpil, Vasquez‐Montes, Victor, Ladokhin, Alexey S., and Thévenin, Damien. 2023. “Promoting the Activity of a Receptor Tyrosine Phosphatase With a Novel <span style=‘font-variant:small-caps;’>pH< Span> ‐responsive Transmembrane Agonist Inhibits cancer‐associated Phenotypes”. https://doi.org/10.1002/pro.4742.
Rizzo, Sophie, et al. Promoting the Activity of a Receptor Tyrosine Phosphatase With a Novel <span style="font-variant:small-caps;">pH< Span> ‐responsive Transmembrane Agonist Inhibits cancer‐associated Phenotypes. 1 Sept. 2023, https://doi.org/10.1002/pro.4742.