ADAM-17: the enzyme that does it all

Abstract

This review focuses on the role of ADAM-17 in disease. Since its debut as the tumor necrosis factor converting enzyme or TACE, ADAM-17 has been reported to be an indispensible regulator of almost every cellular event from proliferation to migration. The central role of ADAM-17 in cell regulation is rooted in its diverse array of substrates: cytokines, growth factors, and their receptors as well as adhesion molecules are activated or inactivated by their cleavage with ADAM-17. It is therefore not surprising that ADAM-17 is implicated in numerous human diseases including cancer, heart disease, diabetes, rheumatoid arthritis, kidney fibrosis, Alzheimer’s disease, and is a promising target for future treatments. The specific role of ADAM-17 in the pathophysiology of these diseases is very complex and depends on the cellular context. To exploit the therapeutic potential of ADAM-17, it is important to understand how its activity is regulated and how specific organs and cells can be targeted to inactivate or activate the enzyme.

Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…Although the molecular mechanism remains to be defined, Drosophila iRhom fulfills a triage role by binding to EGFR ligands and passing them over to the ERAD machinery thereby limiting their availability to active rhomboids Mammalian genomes contain two iRhoms that fulfill redundant, but also, specialized, roles in ADAM17 activation. As well as being the sheddase for EGFR ligands, ADAM17 has numerous substrates, including the inflammatory cytokine, TNF (tumor necrosis factor) [23]. Similar to ADAM17 KO mice, mice deficient for iRhom2 are defective in TNF release from myeloid cells.…”

“…Similar to ADAM17 KO mice, mice deficient for iRhom2 are defective in TNF release from myeloid cells. iRhom2 KO mice respond less severely to sepsis, are protected from experimental arthritis, but exhibit increased sensitivity to Listeria infection, hallmarks of TNF biology [12, [22][23][24]. iRhom redundancy is illustrated by the fact that iRhom single KO mouse embryonic fibroblasts retain substantial ADAM17 activity, whereas ADAM17 is inactive in double knockout (DKO) cells [20,21].…”

Prion and TNFα: TAC(E)it agreement between the prion protein and cell signaling

“…30 In addition to the mentioned pro-TNFα, the cohort of TACE substrates includes receptors for TNFα and other cytokines, cell adhesion molecules and the amyloid precursor protein implicated in Alzheimer disease (AD). 27,28 It seems likely, therefore, that the biological consequences of TACE activity depend on both the nature of the shedded substrate and the cellular context in which TACE operates. [27][28][29] For example, as is the case for TNFα, TACE can generate extracellular soluble messengers that initiate downstream signaling events upon binding to their receptor.…”

A Monoclonal Antibody to ADAM17 Inhibits Tumor Growth by Inhibiting EGFR and Non–EGFR-Mediated Pathways

“…Furthermore,ADAM17 has been implicated in the shedding of HER pathway-independent cytokines, growth factors, receptors, and adhesion molecules (reviewed in ref. 9), many of which have been implicated in cancer development. This HER-independent activity suggests that inhibition of ADAM17 may confer broad antitumor efficacy either as a single agent or in combination with existing HER pathway antagonists targeting HER family receptors.…”