The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation.
The zinc-dependent disintegrin metalloproteinases (a disintegrin and metalloproteinases (ADAMs) have been implicated in several disease processes, including human cancer. Previously, we demonstrated that the expression of a catalytically active member of the ADAM family, ADAM15, is associated with the progression of prostate and breast cancer. The accumulation of the soluble ectodomain of E-cadherin in human serum has also been associated with the progression of prostate and breast cancer and is thought to be mediated by metalloproteinase shedding. Utilizing two complementary models, overexpression and stable short hairpin RNA-mediated knockdown of ADAM15 in breast cancer cells, we demonstrated that ADAM15 cleaves E-cadherin in response to growth factor deprivation. We also demonstrated that the extracellular shedding of E-cadherin was abrogated by a metalloproteinase inhibitor and through the introduction of a catalytically inactive mutation in ADAM15. We have made the novel observation that this soluble E-cadherin fragment was found in complex with the HER2 and HER3 receptors in breast cancer cells. These interactions appeared to stabilize HER2 heterodimerization with HER3 and induced receptor activation and signaling through the Erk pathway, supporting both cell migration and proliferation. In this study, we provide evidence that ADAM15 catalyzes the cleavage of E-cadherin to generate a soluble fragment that in turn binds to and stimulates ErbB receptor signaling.
Najy
Abdo J
AJ
Department of Urology and Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Day
Kathleen C
KC
Day
Mark L
ML
D051722:ADAM Proteins / Q000737:chemistry*; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019281:Dimerization; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
D051722:ADAM Proteins; D015820:Cadherins; D008565:Membrane Proteins; D012313:RNA; D018719:Erb-b2 Receptor Tyrosine Kinases; C098660:ADAM15 protein, human