Trends in Immunology
ReviewADAM17: a molecular switch to control inflammation and tissue regeneration
Section snippets
The A disintegrin and metalloproteinase (ADAM17) is the prototype of the ADAM family of ectodomain shedding proteases
It is estimated that on platelets, up to 10% of all cell surface proteins are proteolytically cleaved and released into the extracellular space; this percentage is likely to be in the same range for all somatic cells via a process called ectodomain shedding [1]. Shedding of integral membrane proteins is observed mostly for type I and type II transmembrane or GPI-anchored proteins and the cleavage site is generally located in close proximity to the outer surface of the cell membrane. Ectodomain
ADAM17 function in the immune system
Inflammation is characterized by elevated levels of cytokines such as TNFα and IL-6. As outlined below, ADAM17 impacts the biology of TNFα and IL-6, which led to the speculation that inhibition of this metalloprotease might have beneficial effects in autoimmune diseases [6].
In the mouse, blockade of TNFα or inhibition of TNFα shedding results in survival of otherwise lethal LPS-induced septic shock [7]. Unfortunately, use of neutralizing anti-TNFα monoclonal antibodies (mAbs) in clinical trials
ADAM17 and cancer
ErbB signaling is involved in the growth of many tumors 28, 29. ADAM17 is upregulated in most tumor cells [28]. In a process called transactivation, shedding of ErbB ligands, e.g. from epithelial cells (Figure 2), by ADAM17 (Table 1) is necessary for appropriate stimulation of ErbB [30]. ADAM17-mediated shedding of ErbB ligands is required for growth of lung carcinoma cells. Surprisingly, on the same cells ADAM17 cleaves Notch1 and the subsequent γ-secretase-mediated release of the
Studying ADAM17 activity in vivo
ADAM17-deficient mice have defects in the mammary epithelium, vascular system, lung, eye, hair, heart and skin and as a result die between embryonic day 17.5 and the first few days after birth [36]. This is reminiscent of ErbB ligand-deficient mice, indicating the importance of the ADAM17−ErbB axis during development [36]. The small subpopulation of ADAM17-deficient mice that survive have reduced lymphocyte numbers, impaired T and B cell development, reduced body weight and an overall
Regulation of ADAM17 activity
Given the importance of cytokine and cytokine receptor shedding for activation of the immune system, it is important to understand how shedding is regulated at the cellular level (reviewed in [45]). ADAM17 is expressed and upregulated in tumor cells almost ubiquitously; however, the involvement of the tumor microenvironment for regulation of ADAM17 expression is not known.
The phorbol ester phorbol 12-myristate 13-acetate (PMA) is a potent activator of ADAM17. PMA induces phosphorylation of PKC
Concluding remarks: ADAM17 and control of inflammatory and regenerative responses
Activation of ADAM17 is activated by signals such as MAP kinases, PKCs and activated oncogenes. Activated ADAM17 is capable of controlling pathways that are biologically distinct. On one hand, cleavage of substrates, including TNFα, IL-6R and L-selectin, can be considered pro-inflammatory because they stimulate both innate and acquired immune responses (Figure 3). On the other hand, activation of the ErbB pathway via trans-activation and via Notch1 cleavage has different consequences (Figure 3
Acknowledgments
The work described in this Review was funded by grants from the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841, project C1 and SFB877, project A1 and A2) and by the Cluster of Excellence ‘Inflammation at Interfaces’.
References (90)
Deciphering the human platelet sheddome
Blood
(2011)Inhibition of the tumor necrosis factor-a-converting enzyme by its pro domain
J. Biol. Chem.
(2004)The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events
J. Biol. Chem.
(2007)The ADAM metalloproteinases
Mol. Aspects Med.
(2008)ADAM17-deficiency by mature neutrophils has differential effects on L-selectin shedding
Blood
(2006)Leukocyte migration is regulated by L-selectin endoproteolytic release
Immunity
(2003)Apoptosis is a natural stimulus of IL6R shedding and contributes to the pro-inflammatory trans-signaling function of neutrophils
Blood
(2007)Attractive shedding
Blood
(2007)Multiple mechanisms are responsible for transactivation of the epidermal growth factor receptor in mammary epithelial cells
J. Biol. Chem.
(2008)- et al.
Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation
Mol. Cell
(2010)