We have shown that the integrin binding to ACE2, but not ACE, is essential for the role of ACE2 as a cellular anchor when expressed on the cell surface. What is more, the presence of ACE2 on the cell surface partially removed the requirement of RGDinteractions for cellular adhesion. Fibroblast motility is a key process in the development of scar tissue and thus cellular adhesion is an important homeostatic mechanism. In order to study the role of ACE and ACE2 in the remodelling response, primary cardiac myofibroblasts were used as a disease model. These cells play a key role in the maintenance of cardiac architecture under conditions of injury, by forming scar tissue through their ability to proliferate and adhere [47] . We demonstrate that both ACE and ACE2 exert comparable effects over myofibroblast adhesion, but that again this effect is not mediated through an RGD motif. Recent clinical investigations have highlighted that elevated levels of sACE2 in patient plasma correlated with increased myocardial dysfunction [29] and vascular compliactions in type 1 diabetes [48] . We have shown that both ACE and ACE2 interact with the cell surface in adhesion assays and, furthermore, ACE2, in particular, enhances cell adhesion and may modulate integrin signalling. Cellular retention of ACE2 is therefore required for its role as a cellular anchor and, as such, the cleavage of ACE2 by ADAM17 [49] may be a pathological step in the development of heart failure. The Figure 2 . Both angiotensin converting enzymes bind integrins independent of an RGD motif. A) Immunoprecipitation of ITGB1 with tACE in HEK-tACE cells. HEK cell lysates were incubated with ITGB1 antibody and eluted using protein G. Immunoblotting for ACE was performed with anti-ACE mC5 antibody. This interaction was similar to that between ACE2 and ITGB1 in ACE2 over-expressing cells. B) Immunoprecipitation of ITGB1 and ITGA5 with tACE in SHSY5Y cells over-expressing the testicular form of ACE. Immunoprecipitation was performed as before. C) Immunoprecipitation of ACE2 with ITGB1 in the presence of a RGD peptide. Huh7 cells were pre-incubated and crosslinked using DTBP, in the presence or absence of RGD peptide before lysis and immunoprecipitation as before. D) Immunoprecipitation of ITGA2, ITGA5, ITGB1 with ACE2 in Huh7 cell monolayers. Cell monolayers were cross-linked using DTBP before lysis and immunoprecipitation as before. doi:10.1371/journal.pone.0034747.g002 retention of ACE2 on the cell membrane is known to be regulated by cell signalling [24] and viral infection [50] . Shed ACE2 could activate integrins by binding to them and transducing activating signals or, additionally, by interacting with non-integrin sites given the multiple protein-protein interactions with which the ACE2 protein is involved.