Figure 2. ADAM17 mediates cardiovascular diseases via ectodomain shedding.

A variety of substrates including growth factors, cytokines, receptors, adhesion molecules are cleaved by ADAM17 and initiate or modulate intracellular signaling. The ectodomain sedding events can be occurred in cis (on the same cell) or trans (between two cells), and act in autocrine (on the same cell types), paracrine (on distinct resident cells) and/or endocrine (on distinct organs through circulation) manner. Therefore, these events involve single cell membrane (cis cleavage and autocrine signaling), two (cis and paracrine/endocrine or trans and paracrine) or three distinct cell-type membranes (trans and endocrine) expressing ADAM17, substrates and the receptors. Prototypical examples of ADAM17 substrate relationship are illustrated. Left: Upon ADAM17 activation, cleaved EGFR ligands transactivate EGFR and initiate EGFR-mediated intracellular signaling including activation of ERK, Akt, mTOR and p70 S6K, resulting in cell proliferation or hypertrophy in an autocrine manner. In addition, the cytoplasmic tail of EGFR ligands is recognized as a site of protein interaction or translocate to nucleus which acts as a transcriptional modulator. Right: Activated ADAM17 also regulate inflammation via the cleavages of inflammatory cytokines and their receptors. The examples shown are proTNF-α shedding and TNFR activation as well as soluble IL6R (sIL6) generation to lead to the IL6-sIL6 complex, which can activate their receptor, GP130 in the absence of IL6R in a paracrine or endocrine manner.