Sheddases cleave membrane proteins at the cell surface, releasing soluble
ectodomains with altered location and function. Some sheddases are membrane
proteins themselves that belong to metalloprotease (ADAM and MMP) or aspartic
protease (BACE) families. Their activity can be constitutive or regulated through
various processes such as PKC activation, Ca2+ influx, and lipid rafts.1-3
A single sheddase may cleave a variety of substrates. A classic example in
this category, ADAM17, was initially identified as TNF-alpha-converting Enzyme
(TACE), and is known to shed a variety of growth factors, receptors, and adhesion
molecules.1,4 This suggests that overall conformations of the substrates
are more important than primary amino acid sequences in determining the accessibility
for cleavage by sheddases.
Multiple sheddases can cleave the same substrate. Under certain circumstances
this may result in different consequences. ADAM17, ADAM10, and MMP-14/MT1-MMP
are all known to shed CD44, an adhesion molecule that interacts with hyaluronic
acid in the ECM.2 Additionally, amyloid precursor protein (APP) processing
by alpha, or by beta- and gamma-secretases has differential effects on the production
of alpha beta peptide, a major plaque component found in brains of Alzheimer’s
disease patients. Cleavage of APP by beta-secretase (BACE-1 and -2) creates
a substrate for gamma-secretase, resulting in alpha beta peptide production.
In contrast, alpha-secretase (ADAM10,
17 and 9) cleavage between the beta- and gamma-secretase sites prevents alpha
beta peptide production.5 Juxtamembrane cleavage that creates a substrate
for further processing that results in the release of a cytoplasmic domain has
been termed regulated intramembrane proteolysis (RIP). Notch processing by ADAM10
RIP liberates the Notch intracellular domain, allowing it to translocate to the
nucleus and activate the transcription of target genes.6
|Figure 1. Diagram illustrating how sheddases alter
ligand (left) or receptor (right) location and function.
Sheddases can act as “thermostats” that either up- or down-regulate
the activity of their substrates. Using a transmembrane ligand/receptor as an
example, shedding may remove/terminate the molecule locally, yield a decoy that
sequesters soluble counterparts, or transduce a signal in conjunction with RIP
as described above (Figure 1). The SARS-CoV receptor, also known as ACE-2, is
shed by ADAM17 and the soluble ACE-2 is able to block cell binding by SARS-CoV
spike protein.7 Similarly, several soluble cytokine receptors, such
as sIL-15 R,8 compete with membrane-bound receptors, while others
including sIL-6 R,9 remain
agonistic when cytokine is bound.
Sheddases can also act as “travel agents,” regulating cell adhesion
and migration. For example, CD44-dependent cell migration is proposed to occur
by ADAM17-mediated CD44 ectodomain shedding at the leading edge of the cell.
Extension of the lamellipod triggers Ca2+ influx, and CD44 shedding
by Ca2+ -activated
ADAM10 at the trailing edge facilitates detachment. RIP creates a cytoplasmic
CD44 fragment that promotes new CD44 synthesis. This link between CD44 proteolysis
and new transcription results in rapid turnover of CD44, facilitating efficient
cell migration.2 Similar models also fit with currently available
data for L-selectin,4
E-Cadherin/beta-catenin,10 NCAM-L1,11 and other adhesion
molecules. Soluble adhesion ectodomains can be functional; sL-selectin directs
migration of activated leukocytes,12 while sE-cadherin causes scattering
of epithelial cells and induction of invasion.10 Association of transmembrane
Ephrins and their Eph receptors on opposing cells often results in cell-cell
repulsion. New data on ADAM10 shedding of Ephrin/Eph complex has explained this
paradox.13 Associated with Eph on one
cell surface, ADAM10 cleaves Ephrin within the Ephrin/Eph complex formed between
two cell surfaces. When ephrin is freed from the opposing cell, the entire Ephrin/Eph
complex is endocytosed. This shedding in trans had not been previously shown,
but may well be involved in other shedding events.
- Moss, M. L. & J. W. Bartsch (2004) Biochemistry 43:7227.
- Nagano, O. & H. Saya (2004) Cancer Sci. 95:930.
- Blobel, C. P. (2005) Nat. Rev. Mol. Cell Biol. 6:32.
- Smalley, D. M. & K. Ley (2005) J. Cell Mol. Med. 9:255.
- Allinson, T. M. J. et al. (2003) J. Neurosci. Res. 74:342.
- Six, E. et al. (2003) Proc. Natl. Acad. Sci. U.S.A. 100:7638.
- Lambert, D. W. et al. (2005) J. Biol. Chem. 280:30113.
- Budagian, V. et al. 2004) J. Biol. Chem. 279:40368.
- Marin, V. et al. (2002) Eur. J. Immunol. 32:2965.
- Maretzky, T. et al. (2005) Proc. Natl. Acad. Sci. U.S.A. 102:9182.
- Maretzky, T. et al. (2005) Mol. Cell. Biol. 25:9040.
- Venturi, G. M. et al. (2003) Immunity 19:713.
- Janes, P. W. et al. (2005) Cell 123:291.