[Frontiers in Bioscience 17, 1948-1964, January 1, 2012]

Soluble E-cadherin: more than a symptom of disease

Magdalena M. Grabowska1, Mark L. Day1

1Program in Cell and Molecular Biology and the Department of Urology, University of Michigan, Ann Arbor


1. Abstract
2. Introduction
2.1. Epithelial cadherin
2.2. E-cadherin cleavage
3. Generation of SE-CAD
3.1. Membrane sheddases
3.1.1. ADAM family
3.1.2. Bacterial proteases (Gingipains and BFT/fragilysin)
3.1.3. Cathepsin family
3.1.4. Kallikrein-7
3.1.5. MMP family
3.1.6. Plasmin
3.1.7. Unattributed sheddases activity
3.2. Proteolytic cascades
4. SE-CAD is present in patient fluids in a variety of conditions
4.1. Cancer
4.1.1. Bladder
4.1.2. Colorectal
4.1.3. Esophageal squamous cell carcinoma
4.1.4. Gastric
4.1.5. Liver
4.1.6. Non-epithelial
5.1.7. Non-small cell lung
5.1.8. Ovarian
5.1.9. Prostate
5.1.10. Skin
4.2. Non-cancer
4.3. Infection
4.4. Organ dysfunction
5. Consequences of SE-CAD presence
5.1. Disruption of cell-cell interactions
5.2. Invasion and migration
5.3. Signaling, proliferation, and survival
6. Discussion
7. References


Epithelial (E)-cadherin is a homophilic adhesion molecule which is responsible for maintenance of baso-lateral cell adhesion and polarity. E-cadherin can be lost from the cell surface by proteolytic cleavage, resulting in the generation of an 80kDa fragment referred to a soluble E-cadherin (sE-cad). Although originally discovered in the conditioned media of breast cancer cells and later verified in the fluids of cancer patients, today sE-cad has been reported in patients with viral and bacterial infections, organ failure, and benign disease. The proteases implicated in this cleavage event include members of the disintegrin family (ADAM10 and 15), bacterial proteases (gingipains and BFT), cathepsins (B, L, S), matrix metalloproteases (MMP-2, 3, 7, 9, and 14), Kallikrein-7 (KLK7), and plasmin. Stimulus that induces sE-cad generation by ADAMs, MMPs, KLK7, and plasmin in vitro ranges from serum withdrawal to pro-inflammatory cytokines to growth factors. The cellular or physiologic consequences of sE-cad accumulation include the disruption of adherens junctions, cellular migration and invasion, induction of MMPs, as well as cell signaling, suggesting that sE-cad may contribute to disease progression.