Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase.
A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as 'ectodomain shedding', under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK. D.Nath@uea.ac.uk
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D001665:Binding Sites; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008666:Metalloendopeptidases / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3; D014407:Tumor Cells, Cultured
D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D019717:Tissue Inhibitor of Metalloproteinase-3; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D008666:Metalloendopeptidases; D019204:GTP-Binding Proteins