Published 24 October 2005. doi:10.1083/jcb.200502013
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 2, 337-348
Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth
Guido Pante1,
Jane Thompson2,
Fabienne Lamballe3,
Tomoko Iwata4,
Ingvar Ferby1,
Francis A. Barr5,
Alun M. Davies6,
Flavio Maina3, and
Rüdiger Klein1
1 Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, 82152 Munich-Martinsried, Germany
2 Fujisawa Institute of Neuroscience, Edinburgh EH8 9JE, Scotland, UK
3 INSERM UMR 623, Developmental Biology Institute of Marseille, 13288 Marseille, Cedex 09, France
4 Division of Cancer Sciences and Molecular Pathology, Faculty of Medicine, University of Glasgow, Beatson Laboratories, Bearsden, Glasgow G61 1BD, Scotland, UK
5 Intracellular Protein Transport Independent Junior Research Group, Max Planck Institute of Biochemistry, 82152 Munich-Martinsried, Germany
6 School of Biosciences, Cardiff CF103US, Wales, UK
Correspondence to Rüdiger Klein: rklein{at}neuro.mpg.de
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.
Abbreviations used in this paper: Ack, activated Cdc42-associated tyrosine kinase; Cdc42*, dominant-active Cdc42; CRIB, Cdc42/Rac interactive binding; FGF2, fibroblast growth factor 2; Grb2, growth factor receptor–bound protein 2; HGF, hepatocyte growth factor; LacZV5, V5 epitope–tagged ß-galactosidase; Mig6, mitogen-inducible gene 6; Mig6FL, full-length Mig6; Mig6FL-V5, SDF-1, stromal cell–derived factor 1; V5 epitope–tagged versions of Mig6; PI3, phosphatidyl-inositol 3; siRNA, small interfering RNA.
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