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Adam17

Domain

Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR.

The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

Function

Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Plays a role in the proteolytic processing of ACE2 (By similarity). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:10799547, PubMed:11108241). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:10882063). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (PubMed:12907434). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (PubMed:17245433). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (By similarity). Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells.

Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins including adhesion proteins, growth factor precursors and cytokines important for inflammation and immunity (PubMed:10799547, PubMed:10882063). Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface. Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:10799547, PubMed:11108241). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:10882063). Plays a role in the proteolytic processing of ACE2 (By similarity). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (PubMed:12907434). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (PubMed:17245433). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R. Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (By similarity).

Post-translational modifications

The precursor is cleaved by a furin endopeptidase.

Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-822 but decreases phosphorylation of Ser-794. Phosphorylation at Thr-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding (By similarity).

Tissue Specificity

Ubiquitously expressed. Expressed at highest levels in heart, liver, skeletal muscle, kidney and testes. Expressed at lower levels in brain, spleen and lung.

Cellular localization

Alternative names

CD156b, Tace, Adam17, Disintegrin and metalloproteinase domain-containing protein 17, ADAM 17, TNF-alpha convertase, TNF-alpha-converting enzyme

swissprot:Q9Z0F8 entrezGene:11491

Other research areas