Protease-activated receptors (PARs) in cancer: Novel biased signaling and targets for therapy.

Abstract

Despite the fact that G protein-coupled receptors (GPCRs) mediate numerous physiological processes and represent targets for therapeutics for a vast array of diseases, their role in tumor biology is under appreciated. Protease-activated receptors (PARs) form a family which belongs to GPCR class A. PAR1&2 emerge with a central role in epithelial malignancies. Although the part of PAR1&2 in cancer is on the rise, their underlying signaling events are poorly understood. We review hereby past, present, and future cancer-associated PAR biology. Mainly, their role in physiological (placenta-cytotophobalst) and patho-physiological invasion processes. The identification and characterization of signal pleckstrin homology (PH)-domain-binding motifs established critical sites for breast cancer growth in PAR1&2. Among the proteins found to harbor important PH-domains and are involved in PAR biology are Akt/PKB as also Etk/Bmx and Vav3. A point mutation in PAR2, H349A, but not R352A, abrogated PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumor growth in vivo as also placental extravillous trophoblast (EVT) invasion in vitro is markedly reduced. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind PH-domain, inhibits mammary tumors and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes.

• Authors: R Bar-Shavit, M Maoz, A Kancharla, M Jaber, D Agranovich, S Grisaru-Granovsky, B Uziely
• Journal: Methods in cell biology (Methods Cell Biol) Vol. 132 Pg. 341-58 ( 2016) ISSN: 0091-679X [Print] United States
• PMID: 26928551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Receptors, Proteinase-Activated

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Female
• Humans
• Molecular Targeted Therapy
• Receptors, Proteinase-Activated (metabolism)
• Signal Transduction (drug effects)