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

Miles A Miller, Aaron S Meyer, Michael T Beste, Zainab Lasisi, Sonika Reddy, Karen Jeng, Karen W Jeng, Chia‐Hung Chen, Chia-Hung Chen, Jongyoon Han, Keith Isaacson, Linda G Griffith, Douglas A Lauffenburger
Proceedings of the National Academy of Sciences of the United States of America · 2013 · vol. 110(22) , pp. E2074–83 · doi:10.1073/pnas.1222387110 · PMID:23674691 · W2137349561
article OA: bronze CC0 ⤵ 17 in-corpus citations
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ADAM-10 and -17 regulate endometriotic cell migration through feedback mechanisms involving ligand release and RTK shedding, with combination inhibition overcoming acquired resistance.

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Abstract

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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

ADAM Proteins Amyloid Precursor Protein Secretases Cell Movement Endometriosis MAP Kinase Signaling System Membrane Proteins Proteolysis ADAM10 Protein ADAM17 Protein ADAM Proteins Amyloid Precursor Protein Secretases Ascitic Fluid Ascitic Fluid Cell Line Cell Movement Computational Biology Computational Biology Endometriosis Feedback, Physiological Feedback, Physiological

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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