218 Chapter 7 et al. demonstrated that lysophosphatidic acid (LPA), a serum phospholipid and GPRC ligand, and EGF, a mitogenic growth factor acting through transmembrane tyrosine kinase receptors, increase MET ectodomain shedding in A549 human lung adenocarcinoma cells. Furthermore, it was shown that both LPA- and EGF-mediated MET ectodomain shedding requires the tyrosine kinase enzymatic activity of EGFR. Additional experiments revealed that LPA mediates transactivation of EGFR through metalloprotease mediated autocrine release of HB-EGF, an EGF family growth factor, from the cell membrane and that MEK inhibitors downregulate both LPA- and EGF-induced MET ectodomain shedding, which is also facilitated by metalloproteases. These experiments suggest that in tumors earmarked by high levels of EGFR activation rates of MET ectodomain shedding increase through activation of the MAPK signaling pathway (48) (Figure 2A). Figure 2: Crosstalk between G-protein-coupled and EGF receptors enhances MET ectodomain shedding. A. GPCR transactivation of EGFR through metalloprotease mediated release of HB-EGF enables MAPK signaling, ultimately resulting in MET ectodomain shedding, which is also facilitated by metalloproteases. B. Overexpression of ADAM10/17 and/or MET in OSCC, will result in the increased concentration of MET-EC- fragments on the tumor cell membrane thus facilitating stabilization (e.g. by dimerization or oligomerization) and constitutive activation of MET-EC-. This figure and its legend, specifically 2A, was inspired by Figure 1 and its legend by Gschwind et al (49). Membranous MET-EC- in OSCC Binding of gastrin-releasing peptide (GRP) to its receptor GRPR, which is a GPCR, facilitates MAPK signaling in the 1483 OSCC cell line through transactivation of EGFR. This is accomplished through metalloprotease-mediated release of TGF-α, the primary autocrine EGFR ligand in HNSCC, from the membrane. Accordingly, inhibition of metalloproteases blocks GRP-mediated EGFR tyrosine phosphorylation (50).
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