EGF promotes the shedding of soluble E-cadherin in an ADAM10-dependent manner in prostate epithelial cells

Abstract

During the progression of prostate cancer, the epithelial adhesion molecule (E)-cadherin is cleaved from the cell surface by ADAM15 proteolytic processing, generating an extracellular 80kDa fragment referred to as soluble E-cadherin (sE-cad). Contrary to observations in cancer, the generation of sE-cad appears to correlate with ADAM10 activity in benign prostatic epithelium. The ADAM10-specific inhibitor INCB8765 and the ADAM10 prodomain inhibit the generation of sE-cad, as well as downstream signaling and cell proliferation. Addition of EGF or amphiregulin (AREG) to these untransformed cell lines increases the amount of sE-cad shed into the conditioned media, as well as sE-cad bound to EGFR. EGF-associated shedding appears to be mediated by ADAM10 as shRNA knockdown of ADAM10 results in reduced shedding of sE-cad. To examine the physiologic role of sE-cad on benign prostatic epithelium, we treated BPH-1 and large T immortalized prostate epithelial cells (PrEC) with an sE-cad chimera comprised of the human Fc domain of IgG1, fused to the extracellular domains of E-cadherin (Fc-Ecad). The treatment of untransformed prostate epithelial cells with Fc-Ecad resulted in phosphorylation of EGFR and downstream signaling through ERK and increased cell proliferation. Pre-treating BPH-1 and PrEC cells with cetuximab, a therapeutic monoclonal antibody against EGFR, decreased the ability of Fc-Ecad to induce EGFR phosphorylation, downstream signaling, and proliferation. These data suggest that ADAM10-generated sE-cad may have a role in EGFR signaling independent of traditional EGFR ligands.

Phase II trial of dacomitinib in patients with HER2-positive gastric cancer

“…The ectodermal shedding of a stable 80-kDa sECAD has been shown to increase in the serum of cancer patients [28]; sECAD is disruptive to cell contact by inducing scattering and eroding the adherens junction by antagonizing full-length E-cadherin. EGF promotes the shedding of sECAD in an ADAM (a disintegrin and metalloprotease) family member-dependent manner, and this sECAD may act in EGFR signaling independently of traditional EGFR ligands [29,30]. Furthermore, in growth factor deprivation states, ADAM15 cleaves E-cadherin and this sECAD is found in complex with the HER2 and HER3 receptors.…”

Nuclear Signaling from Cadherin Adhesion Complexes

“…There are reports of extracellular proteases such as ADAMs and MMPs being involved, as well as intramembrane or intracellular proteases whose activities can be coupled to the initial occurrence of extracellular cleavage events, for example, cleavages subsequently occurring via presenilins or caspases (Damsky, Richa, Solter, Knudsen, & Buck, 1983; De Wever et al, 2007; Dusek et al, 2006; Lochter et al, 1997; Marambaud et al, 2002; Maretzky, Reiss, et al, 2005; Maretzky, Schulte, et al, 2005; McCusker, Cousin, Neuner, & Alfandari, 2009; Noe et al, 2001; Steinhusen et al, 2001; Symowicz et al, 2007; Vallorosi et al, 2000; reviewed in David & Rajasekaran, 2012; McCusker & Alfandari, 2009; Niessen et al, 2011). We will focus upon the intracellular cadherin fragments, but some of the extracellular cleavage products also appear to have biological activity in both development and pathology, for example, in relation to RTK activation (e.g., ErbB/HER2:HER3) and the consequent upregulation of MMP activity or inhibition of apoptosis (Fedor-Chaiken, Hein, Stewart, Brackenbury, & Kinch, 2003; Najy, Day, & Day, 2008; Inge et al, 2011; Grabowska, Sandhu, & Day, 2012; Nawrocki-Raby et al, 2003; Zuo et al, 2011). Further, in vivo exogenous expression of the ectodomain fragment of C-cadherin, for example, disrupts early gastrulation movements in Xenopus , an effect that may take place via altered aPKC and Rac activity in the recipient cells expressing endogenous intact C-cadherin (Seifert, Ibrahim, Stodtmeister, Winklbauer, & Niessen, 2009).…”

Dishonorable Discharge: The Oncogenic Roles of Cleaved E-Cadherin Fragments

“…The link between sE-cad and EGFR also seems to be a reciprocal relationship in which EGFR activation promotes MMP- and ADAM-dependent generation of sE-cad (32, 33). This suggests that a feedback mechanism exists whereby EGFR activation produces sE-cad which can then further activate EGFR signaling to continuously promote oncogenic proliferation and invasion (Fig.…”