The Listeria protein internalin B mimics hepatocyte growth factor-induced receptor trafficking.
Increased hepatocyte growth factor receptor (HGFR) signaling correlates closely with neoplastic invasion and metastatic potential of many human cancers. Hepatocyte growth factor receptor signaling is initiated by binding the physiological ligand HGF or the internalin B (InlB) protein of Listeria monocytogenes. Subsequent degradation of endocytosed HGFR terminates receptor signaling. Previously reported discrepancies in InlB and HGF-induced HGFR signaling could reflect differences in receptor internalization and degradation in response to these distinct ligands. We report that soluble InlB and HGF are mechanistically equivalent in triggering clathrin-dependent endocytosis and lysosomal degradation of HGFR. After internalization, InlB and HGF colocalize with Rab5, EEA1 and the transferrin receptor in classical early endosomes. Hepatocyte growth factor receptor internalization was prevented by overexpression of dominant negative mutants of dynamin 1 and epidermal growth factor phosphorylation substrate 15, but not caveolin 1, the GTPase Arf6 or the cholesterol-chelating drug Nystatin. Thus, HGFR internalization is principally clathrin-mediated and is not regulated by clathrin- independent pathways. Phosphatidylinositol 3-kinase signaling and HGF-regulated tyrosine kinase substrate were not required for ligand-triggered internalization of HGFR but were essential for subsequent lysosomal degradation. Thus, soluble InlB and HGF induce HGFR endocytosis and degradation by indistinguishable mechanisms, suggesting that InlB may be exploited to regulate pathogenic HGFR signaling.
Li
Ning
N
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1043, USA.
Xiang
Guang-Sheng
GS
Dokainish
Hatem
H
Ireton
Keith
K
Elferink
Lisa A
LA
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins / Q000378:metabolism* / Q000502:physiology*; D001710:Biotin / Q000737:chemistry; D019921:Biotinylation; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D034284:Dynamin I / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005799:Genes, Dominant; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008087:Listeria / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D018613:Microscopy, Confocal; D009761:Nystatin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D001710:Biotin; D002135:Calcium-Binding Proteins; D002784:Cholesterol; D002966:Clathrin; D034284:Dynamin I; D020558:GTP Phosphohydrolases; D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D009761:Nystatin; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C486206:EPS15 protein, human; C095768:inlB protein, Listeria monocytogenes; C000715348:ARF6 protein, human