Graduate Student Eden Sikorski

"Promoting the Activity of Receptor Protein Tyrosine Phosphatases with Transmembrane-Binding Peptides"

Cell signaling by receptor protein tyrosine kinases (RTKs) is tightly controlled by the counterbalancing actions of receptor protein tyrosine phosphatases (RPTPs), which dephosphorylate regulatory tyrosine residues on RTKs to attenuate their signal initiating potency. Interestingly, whereas RPTPs can act as suppressors of several tumors, including colon, lung, breast, and thyroid cancers, they can also act as oncogenes when deregulated. The family of RPTPs have therefore long been viewed as potential therapeutic targets, yet the mechanisms controlling their enzymatic activity remains unclear. However, the reported ability of homodimerization to antagonize the activity of RPTPs appears to be a general feature of the entire family.1 The transmembrane domain has been proposed to be involved in their homodimerization2-4, but there is no structure-based theory for how this occurs. We have shown that the transmembrane domain of protein tyrosine phosphatase receptor J (PTPRJ) self-associates through specific amino acid residues.5 Furthermore, creating point mutations of these critical residues in the transmembrane domain destabilizes PTPRJ’s oligomerization, thereby enhancing its phosphatase activity.5 Using these findings, we designed a synthetic peptide agonist that modulates PTPRJ activity by disrupting its self-association through specific transmembrane domain interactions.5 To improve the efficacy of the initial peptide, we have recently engineered a pH sensitive second-generation peptide binder capable of specifically promoting the activity of PTPRJ in cancer cells. The basic framework developed here can be extended to other RPTPs as a new approach to study RPTP activity—and represents a novel class of therapeutics against RTK-driven cancers.

1. Barr A. J., Ugochukwu E., Lee W. H., King O. N. F., Filippakopoulos, P., Alfano, I., Savitsky, P., Burgess-Brown, N. A., Müller, S., Knapp, S. Cell. 2009, 136(2), 352–363.
2. Tertoolen L. G., Blanchetot, C., Jiang, G., Overvoorde, J., Gadella, T. W., Hunter, T., Den Hertog, J. BMC Cell Biol. 2001, 2(8).
3. Chin, C-N., Sachs, J. N., Engelman, D. M. FEBS Lett. 2005, 579(17), 3855–3858.
4. Takeda, A., Matsuda, A., Paul, R. M. J., Yaseen N. R. Blood. 2004, 103(90), 3440–3447.
5. Bloch, E., Sikorski, E. L., Pontoriero, D., Day, E. K., Berger, B. W., Lazzara, M. J., and Thévenin, D. J Biol Chem. 2019, 294(49), 18796-18806.