Journal Article

ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling

Miles A. Miller, Zainab Lasisi, Karen W. Jeng, Aaron S. Meyer, Chia-Hung Chen, Sonika Reddy, Michael T. Beste, Jongyoon Han, Keith Isaacson, Linda G. Griffith, Douglas A. Lauffenburger

2013

Overview

A Disintegrin and Metalloproteinases (ADAMs) are the principal enzymes for shedding receptor tyrosine kinase (RTK) ectodomains and ligands from the cell surface. Multiple layers of activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent ADAM “sheddase” function and our ability to predictably target that function in disease. This study uses combined measurement and computational modeling to examine how various growth factor environments influence sheddase activity and cell migration in the invasive disease of endometriosis. We find that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct cell motility. Data-driven modeling reveals that induced cell migration is a quantitative function of positive feedback through EGF ligand release and negative feedback through RTK shedding. Although sheddase inhibition prevents autocrine ligand shedding and resultant EGF receptor transactivation, it also leads to an accumulation of phosphorylated receptors (HER2, HER4, and MET) on the cell surface, which subsequently enhances Jnk/p38 signaling. Jnk/p38 inhibition reduces cell migration by blocking sheddase activity while additionally preventing the compensatory signaling from accumulated RTKs. In contrast, Mek inhibition reduces ADAM-10 and -17 activities but fails to inhibit compensatory signaling from accumulated RTKs, which actually enhances cell motility in some contexts. Thus, here we present a sheddase-based mechanism of rapidly acquired resistance to Mek inhibition through reduced RTK shedding that can be overcome with rationally directed combination inhibitor treatment. We investigate the clinical relevance of these findings using targeted proteomics of peritoneal fluid from endometriosis patients and find growth-factor–driven ADAM-10 activity and MET shedding are jointly dysregulated with disease.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: ADAM Proteins - metabolism / ADAM10 Protein / ADAM17 Protein / Amyloid Precursor Protein Secretases - metabolism / Ascitic Fluid - metabolism / autocrine signaling / Biological Sciences / Cell adhesion & migration / Cell Line / cell movement / Cell Movement - physiology / Cells / Computational Biology - methods / Endometriosis / Endometriosis - physiopathology / epidermal growth factor receptors / Feedback, Physiological - physiology / Female / Humans / Kinases / ligands / MAP Kinase Signaling System - physiology / Membrane Proteins - metabolism / metalloproteinases / Microscopy, Electron, Transmission / Models, Biological / patients / PNAS Plus / Proteolysis / Proteomics / Proto-Oncogene Proteins c-met - metabolism / Signal transduction / T cell receptors / transcriptional activation