Scramblases as Regulators of Proteolytic ADAM Function

Abstract

Proteolytic ectodomain release is a key mechanism for regulating the function of many cell surface proteins. The sheddases ADAM10 and ADAM17 are the best-characterized members of the family of transmembrane disintegrin-like metalloproteinase. Constitutive proteolytic activities are low but can be abruptly upregulated via inside-out signaling triggered by diverse activating events. Emerging evidence indicates that the plasma membrane itself must be assigned a dominant role in upregulation of sheddase function. Data are discussed that tentatively identify phospholipid scramblases as central players during these events. We propose that scramblase-dependent externalization of the negatively charged phospholipid phosphatidylserine (PS) plays an important role in the final activation step of ADAM10 and ADAM17. In this manuscript, we summarize the current knowledge on the interplay of cell membrane changes, PS exposure, and proteolytic activity of transmembrane proteases as well as the potential consequences in the context of immune response, infection, and cancer. The novel concept that scramblases regulate the action of ADAM-proteases may be extendable to other functional proteins that act at the cell surface.

Keywords: ADAM10; ADAM17; activation; cell membrane asymmetry; phosphatidylserine; scramblases.

Figure 1

Proposed links between scramblase and ADAM17 function. (a) In non-activated cells, negatively charged phosphatidylserine (PS, red) is mainly sequestered in the inner cell membrane leaflet, while phosphatidylcholine (yellow) is mainly localized in the exoplasmic leaflet. ADAM17 (blue) has limited access to substrates. The ectodomain consists of a metalloprotease domain, a disintegrin domain, and a membrane-proximal domain (MPD) followed by a stalk region. (b) Cell stimulation can lead to scramblase activation and rapid loss of cell membrane asymmetry. Externalized PS electrostatically interacts with positively charged amino acids of ADAM17 and guides the enzyme to its substrate.

Figure 2

Transient exposure of PS plays an important role in the immune system. One example is the release of the TNFR family member CD137 via ADAM10 (or ADAM17). Soluble CD137 (sCD137) can bind to its ligand CD137L expressed on activated T cells and activate cell signaling. Whether sCD137 could fulfill additional functions, e.g., activation of antigen-presenting cells (APCs) or act as decoy is still not clear.

Figure 3

PS externalization could be of high relevance for virus entry into host cells. First, formation of the primary virus–receptor complex triggers non-apoptotic cell surface exposure of PS via scramblases. Externalized PS promotes membrane fusion and virus infection. Second, scramblase activation would lead to ADAM activation. Subsequent EGFR signaling has been identified as important step for infection with the human papillomavirus.