213 MET ECD shedding and use of targeted therapies Figure 1: HGF/MET signaling facilitated invasive growth and presenilin-regulated intramembrane proteolysis (PS-RIP) mediated receptor down-regulation. A. Upon binding by its extracellular ligand, hepatocyte growth factor/scatter factor (HGF/SF), MET signaling facilitates the biological program of invasive growth by activating a complex network of signaling cascades. During invasive growth, cancer cells integrate proliferation, survival, motility, and epithelial-to-mesenchymal transition. HGF binding stimulates the kinase activity of MET through receptor dimerization and trans-phosphorylation of catalytic residues Tyr1234 and Tyr1235. Upon subsequent phosphorylation of the carboxy-terminal ‘docking’ residues Tyr1349 and Tyr1356, MET recruits a multitude of downstream signal-relay transducers. Transduction of most MET-mediated downstream signaling modules is generally regulated by the interaction with the multi-adaptor protein GAB1 (GRB2-associated-binding protein 1). Ultimately, MET and its signal transducers effectively activate downstream signaling pathways, including MAPK, PI3K-Akt, and STAT. B. During presenilin-regulated intramembrane proteolysis (PS-RIP), MET is down-regulated through sequential proteolytic cleavages. The receptor is first cleaved within its juxtamembrane domain by membrane metalloproteases (ADAM10/17). This results in shedding of the soluble ectodomain (MET-NTF), while a residual 55 kDa C-terminal fragment (MET-CTF) remains anchored to the membrane. The resulting 50 kDa intracellular domain of MET (MET-ICD) is released into the cytosol and degraded by the proteasome. The MET-CTF fragments escaping γ-secretase cleavage undergo lysosomal degradation. This figure and its legend, specifically 1A, was inspired by Figure 1 by Trusolino et al. (13), Figure 2 by Gherardi et al. (12), and Figure 5B by Schelter et al. (15), as well as their corresponding legends. Figure 1B and its legend, was inspired by Figure 1A and its legend by Fernandes et al. (16). 7
RkJQdWJsaXNoZXIy MTk4NDMw