title: Met receptor tyrosine kinase degradation is altered in response to the leucine-rich repeat of the Listeria invasion protein internalin B.
abstract: Entry of the bacterial pathogen Listeria monocytogenes into host epithelial cells is critical for infection and virulence. One major pathway for Listeria entry involves binding of the bacterial protein Internalin B to the host receptor tyrosine kinase Met (hepatocyte growth factor receptor). Activation of Met and downstream signaling cascades is critical for Listeria entry. Internalin B is composed of several structural domains including an N-terminal leucine-rich repeat that is sufficient for binding Met and stimulating downstream signal transduction. Internalin B is monomeric, whereas the leucine-rich repeat is dimeric when expressed as an isolated fragment. The different quaternary states of Internalin B and the leucine-rich repeat suggest that these two Met ligands might cause distinct biological effects. Here we demonstrate that Internalin B and the leucine-rich repeat fragment exhibit agonist properties that differentially influence Met down-regulation in lysosomes. Specifically, Met stability is increased in response to the leucine-rich repeat fragment compared with Internalin B. Interestingly, Internalin B and the leucine-rich repeat stimulate equivalent rates of clathrin-mediated Met internalization. However, the leucine-rich repeat is defective in promoting lysosomal down-regulation of Met and instead enhances receptor recycling to the cell surface. In addition, the leucine-rich repeat causes prolonged Met activation (phosphorylation) and increased cell motility compared with Internalin B. Taken together, our findings indicate that individual domains of Internalin B differentially regulate Met trafficking. The ability of the leucine-rich repeat fragment to promote Met recycling could account for the increased cell motility induced by this ligand.
authors.affiliation: Department of Neuroscience and Cell Biology, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1074, USA.
authors.forename: Xiu
authors.initials: X
authors.lastname: Gao
authors.forename: Marta
authors.initials: M
authors.lastname: Lorinczi
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Hill
authors.forename: Natasha C
authors.initials: NC
authors.lastname: Brooks
authors.forename: Hatem
authors.initials: H
authors.lastname: Dokainish
authors.forename: Keith
authors.initials: K
authors.lastname: Ireton
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Elferink
mesh_terms: D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D004285:Dogs; D004705:Endocytosis; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019859:Proto-Oncogene Proteins c-met / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D002966:Clathrin; D008565:Membrane Proteins; C095768:inlB protein, Listeria monocytogenes; D019859:Proto-Oncogene Proteins c-met; D007930:Leucine