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.
Highlights
Membrane anchored metalloproteases of the ADAM family assume central functions in the living cell by the controlled cleavage and release of biologically active proteins and peptides from the membrane surface
We summarize current knowledge regarding the significance of PS externalization on proteolytic activity of ADAM10 and ADAM17
Externalization of PS effected by scramblases is envisaged to exert a key regulatory function in controlling substrate cleavage by ADAM10 and ADAM17
Summary
Membrane anchored metalloproteases of the ADAM family assume central functions in the living cell by the controlled cleavage and release of biologically active proteins and peptides from the membrane surface. ADAM17 is known to be involved in the shedding of an increasing number of cell surface proteins including the EGFR ligands TGF-α and amphiregulin (AREG), TNF receptor 1, and L-selectin. For ADAM17, inactive rhomboid proteins, iRhom and iRhom, are assumed to be key regulators of maturation, protease function and substrate selectivity [15,16,17]. The main thrust of research into the control of sheddase activation has been conducted on these two proteases They have targeted dissection of events underlying the trafficking of the proteases to the cell surface, and of regulatory roles assignable to the extracellular domains of the proteases [28,29]. The potential functional consequences of these interactions are discussed and future challenges to be met in field are outlined
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