Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.
Hepatocyte growth factor (HGF)/Met signaling controls cell migration, growth and differentiation in several embryonic organs and is implicated in human cancer. The physiologic mechanisms that attenuate Met signaling are not well understood. Here we report a mechanism by which mitogen-inducible gene 6 (Mig6; also called Gene 33 and receptor-associated late transducer) negatively regulates HGF/Met-induced cell migration. The effect is observed by Mig6 overexpression and is reversed by Mig6 small interfering RNA knock-down experiments; this indicates that endogenous Mig6 is part of a mechanism that inhibits Met signaling. Mig6 functions in cells of hepatic origin and in neurons, which suggests a role for Mig6 in different cell lineages. Mechanistically, Mig6 requires an intact Cdc42/Rac interactive binding site to exert its inhibitory action, which suggests that Mig6 acts, at least in part, distally from Met, possibly by inhibiting Rho-like GTPases. Because Mig6 also is induced by HGF stimulation, our results suggest that Mig6 is part of a negative feedback loop that attenuates Met functions in different contexts and cell types.
Pante
Guido
G
Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, 82152 Munich-Martinsried, Germany.
Thompson
Jane
J
Lamballe
Fabienne
F
Iwata
Tomoko
T
Ferby
Ingvar
I
Barr
Francis A
FA
Davies
Alun M
AM
Maina
Flavio
F
Klein
Rüdiger
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins