The Ectodomain Shedding of E-cadherin by ADAM15 Supports ErbB Receptor Activation*
By Abdo J Najy, K. Day, M. Day. 2008
193 citations recorded by the source corpus.
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.
Subfields: Immunology and Allergy, Molecular Biology, Oncology
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Citations in the corpus
- A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “ADAM-15 cleaves E-cadherin, thus compromising epithelial and endothelial connections and reducing cell connections and tissue stability, and in turn inducing migration and infiltration of inflammatory cells in the cardiovascular system [76, 77].”
- ADAM15 regulates endothelial permeability and neutrophil migration via Src/ERK1/2 signalling. (2010, methodology): “Serum-free medium was collected and processed as described previously.(18) The level of soluble VE-cadherin was detected using western blotting with an antibody against the extracellular domain of VE-cadherin (R&D, MN, USA).”
- ADAMs family and relatives in cardiovascular physiology and pathology. (2016, background): “ADAM15 can cleave E-cadherin, compromising epithelial and potentially endothelial connections [78,79]which can impact vascular function and infiltration of inflammatory cells.”
- Involvement of members of the cadherin superfamily in cancer. (2009, background): “Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a003129 11 generates a soluble E-cadherin ectodomain (Najy et al. 2008).”
- ADAM and ADAMTS gene expression in native and wound healing human lens epithelial cells (2010, background): “ADAM-15 is implicated in EGFR ligand shedding, possibly through EGFR transactivation [50,51] and catalyzes the shedding of a soluble E-cadherin fragment that is increased during the progression of breast cancer [52].”