ADAM12 is expressed in the tumour vasculature and mediates ectodomain shedding of several membrane-anchored endothelial proteins

Abstract

ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

“…It was shown that ADAM12L controls MMP14 activity through an αvβ3 integrin-dependent mechanism independent of its cytoplasmic tail or catalytic activity. 37 Similarly, ADAM12S may control the activity of E-cadherin sheddases like MMP14; however, our demonstration that ADAM12's catalytic activity is required for E-cadherin shedding, combined with findings showing that ADAM12 directly cleaves several membrane-bound substrates, including the type-II cadherin VE-cadherin, 38 supports a role for direct proteolysis of E-cadherin by ADAM12.…”

ADAM12 and PAPP-A: Candidate regulators of trophoblast invasion and first trimester markers of healthy trophoblasts

“…For example, gene-targeting strategies in mice indicate ADAM12 as a key regulator in myogenesis 12 and adipogenesis, 13 while in vitro studies have assigned roles for ADAM12 in promoting cell fusion in osteoclasts 14 and trophoblasts. 15 ADAM12 also positively associates, and in some cases promotes, the progression of chronic disease states including multiple subtypes of cancer, [16][17][18] fibrosis, 19 and cardiac hypertrophy. 20 The secreted variant, ADAM12S, strongly links with cancer progression where serum levels are elevated in patients with highly-invasive metastatic breast cancer, while ADAM12S over-expression promotes breast cancer cell invasion.…”

“…10 Moreover, ADAM12 has recently been shown to cleave several cell adhesion molecules and components of the Notch signalling pathway, including vascular endothelial cadherin, vascular cell adhesion molecule 1, E-cadherin and delta-like ligand-1 (DLL1) 15,16,24 (Fig. 1).…”

ADAM12: a genetic modifier of preclinical peripheral arterial disease

“…Recent studies by Frohlich et al (12) showed that ADAM12 is expressed on ECs and can mediate ectodomain shedding/ cleavage of a number of EC membrane proteins, including Tie2, vascular endothelial (VE)-cadherin, and VEGFR2, with Tie2 shedding as the most robust of the proteins assessed. Moreover, there is evidence that Tie2 plays a critical role in perfusion recovery following experimental PAD (27), and cleavage of Tie2 leads to Tie2 activation and p-AKT (10,23).…”