Graduate Student Sophie Rizzo

"The Influence of the Structure-Function Relationship on Receptor Protein Signaling"

Protein phosphorylation is a common chemical modification that can be made to a protein after initial synthesis and control its function with the cell. This process is tightly regulated by protein kinases and phosphatases which add, or remove phosphate groups from specific residues on proteins. However, the structural regulation of receptor protein tyrosine phosphatases (RPTPs) remains poorly understood due to the lack of natural ligands or selective drugs. The ability of RPTPs to form homodimers (complex of two of the same protein subunit) thereby inhibiting their catalytic activity presents an opportunity to target dysregulated phosphorylation and cell signaling. We previously demonstrated that the homodimerization of protein tyrosine phosphatase receptor J (PTPRJ) is regulated by specific transmembrane residues. Disrupting these interactions via point mutations or transmembrane-binding peptides reduced homodimerization, promoting the active monomeric form. This increased PTPRJ’s access to receptor tyrosine kinase (RTK) substrates, such as epidermal growth factor receptor (EGFR), leading to reduced EGFR phosphorylation and inhibition of cancer-associated phenotypes (growth, migration, proliferation) across multiple cell lines. To further investigate PTPRJ’s role, we developed a data-driven model predicting phosphorylation-mediated signaling pathways and cancer-associated phenotypes affected by PTPRJ activation. Additionally, we designed a novel class of pH-sensitive peptides that target PTPRJ’s transmembrane domain, and selectively disrupts its homodimerization in the acidic tumor microenvironment. Our lead peptide, Hybrid 7, enhances PTPRJ phosphatase activity and inhibits tumor-promoting signaling. We are now employing high-throughput techniques, such as mass spectrometry proteomics, to assess the broader effects of Hybrid 7 on cell signaling. Our findings provide critical structure-function insights into PTPRJ and other RPTPs, highlighting their therapeutic potential in disease modulation.