EpCAM was found to be overexpressed on epithelial progenitors, carcinomas and cancer-initiating cells. The role of EpCAM in proliferation, and its association with cancer is poorly explained by proposed cell adhesion functions. Here we show that regulated intramembrane proteolysis activates EpCAM as a mitogenic signal transducer in vitro and in vivo. This involves shedding of its ectodomain EpEX and nuclear translocation of its intracellular domain EpICD. Cleavage of EpCAM is sequentially catalysed by TACE and presenilin-2. Pharmacological inhibition or genetic silencing of either protease impairs growth-promoting signalling by EpCAM, which is compensated for by EpICD. Released EpICD associates with FHL2, beta-catenin and Lef-1 to form a nuclear complex that contacts DNA at Lef-1 consensus sites, induces gene transcription and is oncogenic in immunodeficient mice. In patients, EpICD was found in nuclei of colon carcinoma but not of normal tissue. Nuclear signalling of EpCAM explains how EpCAM functions in cell proliferation.

We have identified in organic solvent extracts of whole cells of the gram-positive pathogen Rhodococcus equi two channel-forming proteins with different and complementary properties. The isolated proteins were able to increase the specific conductance of artificial lipid bilayer membranes made from phosphatidylcholine-phosphatidylserine mixtures by the formation of channels able to be permeated by ions. The channel-forming protein PorA Req (R. equi pore A) is characterized by the formation of cation-selective channels, which are voltage gated. PorA Req has a single-channel conductance of 4 nS in 1 M KCl and shows high permeability for positively charged solutes because of the presence of negative point charges. According to the results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the protein has an apparent molecular mass of about 67 kDa. The analysis (using the effect of negative charges on channel conductance) of the concentration dependence of the single-channel conductance suggested that the diameter of the cell wall channel is about 2.0 nm. The second channel (formed by PorB Req [R. equi pore B]) shows a preferred movement of anions through the channel and is not voltage gated. This channel shows a single-channel conductance of 300 pS in 1 M KCl and is characterized by the presence of positive point charges in or near the channel mouth. Based on SDS-PAGE, the apparent molecular mass of the channel-forming protein is about 11 kDa. Channel-forming properties of the investigated cell wall porins were compared with those of others isolated from mycolic acid-containing actinomycetes. We present here the first report of a fully characterized anion-selective cell wall channel from a member of the order Actinomycetales.Rhodococcus equi (formerly Corynebacterium equi) is recognized as a significant cause of disease in foals between the ages of 1 and 6 months and is responsible for ca. 3% of global foal mortality (13,33). This organism was first reported as a cause of human disease in 1967 (14), since which time it has emerged as an opportunistic pathogen, notably (but not exclusively) of patients with compromised immunity (25,27,33,52). Moreover, it is likely that the incidence of human infection by R. equi has been underestimated through either misdiagnosis or unwarranted dismissal of the organism as a contaminant diphtheroid (52).In both foals and humans, R. equi disease is typically characterized by bronchopneumonia, although extrapulmonary manifestations are also found (13, 33, 52). R. equi is an intracellular pathogen of alveolar macrophages, and the bacterium is known to enter macrophages via complement receptors following deposition of complement component C3 (25). Once within the macrophage, the bacteria resist the host's killing mechanisms and multiply. However, there is currently little information concerning the specific bacterial factors which facilitate entry into or subsequent survival within macrophages. Persistence within macrophages most likely contributes to the in vivo ...