216 Chapter 7 Table 1: Corresponding soluble N-terminal and presumed membranous C-terminal MET fragments resulting after ectodomain shedding named after there approximate molecular masses observed under reducing conditions (40, 42). MET N-terminal fragments (MET-NTFs) observed in the culture medium of a breast cancer progression model (40) MET C-terminal fragments (MET-CTFs) observed in OSCC cell lines and fresh frozen tissues (42) p50β p95β p55b p90b p75β p70β p85β p60β *p100β p55b * It should be noted that this fragment should not be mistaken for the 100 kDa fragment observed by Deheuninck et al. (43), as this is a soluble extracellular fragments presumed to be the result of ectodomain shedding instead of the membrane bound extracellular domain of MET. Since the latter N-terminal fragment is able to bind HGF, however it is unable to initiate HGF signaling, due to its lacking kinase domain, it is known as the decoy receptor. MET ectodomain shedding in the tumor suppressive and oncogenic context Concurrent with the view that MET proteolysis likely results from an intrinsic cellular mechanism that attenuates excessive MET signaling (13), it was shown that MET ectodomain shedding augments with increased malignant potential by taking advantage of an in vitro derived breast cancer progression model, (40). However, Kang et al. observed that only C- and not N-terminal MET immunoreactivity was associated with poor prognosis in node-negative breast cancer. Therefore, it was suggested that the overexpression of the MET cytoplasmic-tail may favor breast cancer progression upon proteolytic cleavage or by truncating mutations (44). Accordingly, NIH-3T3 mouse embryo fibroblasts expressing a membrane-bound MET receptor fragment lacking the ectodomain (MET-EC-, +/- p60β) constitutively activated MAPK and PI3KAkt signaling (45). Moreover, MET-EC- expression confers transforming, invasive, and tumorigenic properties to NIH-3T3 cells. Based on the previous observations, it is assumed that MET ectodomain shedding not only suppresses MET signaling by reducing the number of receptor molecules present on the membrane, but it may also give rise to membranous MET-EC- that conveys invasive and aggressive properties to cancer cells, ultimately resulting in poor prognosis.
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