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PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design
PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design
- Source :
- Molecular Cancer Therapeutics. 21:1415-1429
- Publication Year :
- 2022
- Publisher :
- American Association for Cancer Research (AACR), 2022.
-
Abstract
- While the role of G-protein–coupled receptors (GPCR) in cancer is acknowledged, their underlying signaling pathways are understudied. Protease-activated receptors (PAR), a subgroup of GPCRs, form a family of four members (PAR1–4) centrally involved in epithelial malignancies. PAR4 emerges as a potent oncogene, capable of inducing tumor generation. Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical for colon cancer growth. In addition to PH–Akt/PKB association, other PH-containing signal proteins such as Gab1 and Sos1 also associate with PAR4. Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate these associations. Pc(4–4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding motifs. It effectively attenuates PAR2&4–Akt/PKB associations; PAR4 instigated Matrigel invasion and migration in vitro and tumor development in vivo. EGFR/erbB is among the most prominent cancer targets. AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively inhibited by Pc(4–4). The presence of PAR2 and PAR4 in biopsies of aggressive breast and colon cancer tissue specimens is demonstrated. We propose that Pc(4–4) may serve as a powerful drug not only toward PAR-expressing tumors but also for treating EGFR/erbB-expressing tumors in cases of resistance to traditional therapies. Overall, our studies are expected to allocate new targets for cancer therapy. Pc(4–4) may become a promising candidate for future therapeutic cancer treatment.
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....e3fcaa5744d55ebaea04c3a61fe4302a
- Full Text :
- https://doi.org/10.1158/1535-7163.mct-21-0946