The shadow of death on the MET tyrosine kinase receptor

Abstract

The MET tyrosine kinase receptor is a high-affinity receptor for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF-MET system is necessary for embryonic development, and aberrant MET signalling favours tumorigenesis and metastasis. MET is a prototype of tyrosine kinase receptor, which is able to counteract apoptosis through the initiation of a survival signal involving notably the PI3K-Akt pathway. Paradoxically, the MET receptor is also able to promote apoptosis when activated by HGF/SF or independently of ligand stimulation. The molecular mechanisms underlying this uncommon response have been recently investigated and revealed dual antiapoptotic or proapoptotic property of MET according to the cell type or stress conditions. Although the involvement of MET in the regulation of integrated biological responses mostly took into account its efficient antiapoptotic function, its proapoptotic responses could also be important for regulation of the survival/apoptosis balance and play a role during the development or tumour progression.

CD44 Variant Isoforms Promote Metastasis Formation by a Tumor Cell-Matrix Cross-talk That Supports Adhesion and Apoptosis Resistance

“…We noted an increased association between CD44v6 and c-Src in ASML cells, which was accompanied by increased activation of the focal adhesion kinase, 5 which can trigger PI3K activation. It also has been described that c-met supports tumor cell survival via PI3K/Akt activation (45,46) and that c-met interacts with CD44v6 via hepatocyte growth factor/scatter factor binding (23). Notably, c-met activity is significantly reduced in ASML-CD44v kd cells.…”

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

“…We have previously demonstrated that Met is cleaved by caspases, which separate the extracellular ligand-binding domain from the intracellular kinase domain. In addition to abolishing the ligand responsiveness of Met, these cleavages generate a cytoplasmic proapoptotic fragment named p40 Met, involved in apoptosis amplification (Tulasne et al, 2004;Foveau et al, 2007;Deheuninck et al, 2008;Tulasne and Foveau, 2008). Many other fragments of Met have been described, but their biological functions, and the mechanisms involved in their generation have not been investigated.…”

Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab

“…HGF binding results in receptor dimerization, activation, and internalization mediated by the phosphorylation of multiple tyrosine residues in the MET intracellular domain (1)(2)(3)(4)(5)(6). Signaling through MET results in cell survival, proliferation, motility, migration, and complex morphogenetic processes (2,7,8). Although MET signaling is essential for embryonic development and tissue repair in adults (2), aberrant signaling through activating MET mutations (3,4,8), MET overexpression (9,10), or dysregulated autocrine expression of HGF and MET in tumor cells (9)(10)(11)(12)(13) contributes to malignant progression and metastasis of cancer cells (2,7,8).…”