The CD157-Integrin Partnership Controls Transendothelial Migration and Adhesion of Human Monocytes

Abstract

CD157, a member of the CD38 gene family, is an NAD-metabolizing ectoenzyme and a signaling molecule whose role in polarization, migration, and diapedesis of human granulocytes has been documented; however, the molecular events underpinning this role remain to be elucidated. This study focused on the role exerted by CD157 in monocyte migration across the endothelial lining and adhesion to extracellular matrix proteins. The results demonstrated that anti-CD157 antibodies block monocyte transmigration and adhesion to fibronectin and fibrinogen but that CD157 cross-linking is sufficient to overcome the block, suggesting an active signaling role for the molecule. Consistent with this is the observation that CD157 is prevalently located within the detergent-resistant membrane microdomains to which, upon clustering, it promotes the recruitment of ␤ 1 and ␤ 2 integrin, which, in turn, leads to the formation of a multimolecular complex favoring signal transduction. This functional cross-talk with integrins allows CD157 to act as a receptor despite its intrinsic structural inability to do so on its own. Intracellular signals mediated by CD157 rely on the integrin/Src/ FAK (focal adhesion kinase) pathway, resulting in increased activity of the MAPK/ERK1/2 and the PI3K/Akt downstream signaling pathways, which are crucial in the control of monocyte transendothelial migration. Collectively, these findings indicate that CD157 acts as a molecular organizer of signaling-competent membrane microdomains and that it forms part of a larger molecular machine ruled by integrins. The CD157-integrin partnership provides optimal adhesion and transmigration of human monocytes.

Binding of CD157 Protein to Fibronectin Regulates Cell Adhesion and Spreading

“…12, A and B). These results show that engagement of CD157 by fibronectin increases the activation of key adhesion-dependent tyrosine kinases mirroring the effects observed upon CD157 antibody cross-linking (11).…”

“…Moreover, CD157 is part of the integrin-driven molecular machinery that regulates fundamental functions in neutrophils and monocytes through the activation of a complex signaling network (10,11). The ability of CD157 to bind FN suggests that this interaction could account for the receptor activity attributed to CD157.…”

“…1A) to microtiter plates coated with selected human ECM proteins or BSA as control. We first focused on fibronectin, a ubiquitous component of the ECM that plays a crucial role in mediating cell attachment, because of previous evidence underscoring a functional and structural partnership between CD157 and ␤1 (and ␤2) integrin, which are elective receptors for fibronectin (11). Purified rh-sCD157 displayed concentration-dependent binding to FN.…”

“…Since its discovery more than 20 years ago, human CD157 (then known as Mo5) (6) has been implicated in the control of leukocyte migration (7). Subsequently, leukocyte CD157 was found to control adhesion to extracellular matrix (ECM) 4 proteins, directional migration, and diapedesis (8,9) by establishing structural and functional interactions with specific members of the integrin family of adhesion receptors (10,11). Evidence obtained by in vitro experiments and from correlative clinical studies in ovarian cancer patients suggested an important functional link between high expression of CD157 and the malignant phenotype of tumor cells, including their increased motility and invasion of surrounding tissues (12).…”

“…This approach consistently pointed to an important role of CD157 in cell adhesion and migration, but it failed to identify which interactions were instrumental for its receptor activities in normal and pathological conditions. The crucial role of CD157 in cell adhesion, migration and invasion, and its functional partnership with members of the integrin family in myeloid cells (11) fostered the hypothesis that the ligand of CD157 might be found in the ECM.…”