www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 34), pp: 56490-56505 Research Paper Proteolytic cleavages in the extracellular domain of receptor tyrosine kinases by membrane-associated serine proteases Li-Mei Chen1 and Karl X. Chai1 1Burnett School of Biomedical Sciences, Division of Cancer Research, University of Central Florida College of Medicine, Orlando, FL 32816-2364, USA Correspondence to: Karl X. Chai, email:
[email protected] Keywords: receptor tyrosine kinase, matriptase, prostasin, Herceptin, breast cancer Received: August 05, 2016 Accepted: March 21, 2017 Published: April 10, 2017 Copyright: Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The epithelial extracellular membrane-associated serine proteases matriptase, hepsin, and prostasin are proteolytic modifying enzymes of the extracellular domain (ECD) of the epidermal growth factor receptor (EGFR). Matriptase also cleaves the ECD of the vascular endothelial growth factor receptor 2 (VEGFR2) and the angiopoietin receptor Tie2. In this study we tested the hypothesis that these serine proteases may cleave the ECD of additional receptor tyrosine kinases (RTKs). We co-expressed the proteases in an epithelial cell line with Her2, Her3, Her4, insulin receptor (INSR), insulin-like growth factor I receptor (IGF-1R), the platelet-derived growth factor receptors (PDGFRs) α and β, or nerve growth factor receptor A (TrkA). Western blot analysis was performed to detect the carboxyl-terminal fragments (CTFs) of the RTKs. Matriptase and hepsin were found to cleave the ECD of all RTKs tested, while TMPRSS6/matriptase-2 cleaves the ECD of Her4, INSR, and PDGFR α and β.