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Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.

Pante G, Thompson J, Lamballe F, Iwata T, Ferby I, Barr FA, Davies AM, Maina F, Klein R - J. Cell Biol. (2005)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, 82152 Munich-Martinsried, Germany.

ABSTRACT
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.

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Physiologic inhibition of HGF-mediated cell migration by Mig6 is independent of its effects on proliferation. Representative Hoechst dye–labeled MLP29 cells that were transfected with GFP-specific siRNAs (A and C) or Mig6-specific siRNAs (B and D) migrated onto the lower face of the Boyden chamber membrane upon stimulation with HGF. The cells were exposed to media containing DMSO (A and B) or 1.6 μg/ml aphidicolin solubilized in DMSO (C and D). Bar, 100 μm. (E) Quantification of cell migration expressed as fold of induction over unstimulated cells. Migration was enhanced in cells transfected with Mig6 siRNAs (gray bars) compared with GFP siRNAs (black bars) in the absence or presence of aphidicolin (Aphid.) (P = 0.019 and P < 0.0002, respectively, t test). *, P < 0.05; **, P < 0.01.
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fig4: Physiologic inhibition of HGF-mediated cell migration by Mig6 is independent of its effects on proliferation. Representative Hoechst dye–labeled MLP29 cells that were transfected with GFP-specific siRNAs (A and C) or Mig6-specific siRNAs (B and D) migrated onto the lower face of the Boyden chamber membrane upon stimulation with HGF. The cells were exposed to media containing DMSO (A and B) or 1.6 μg/ml aphidicolin solubilized in DMSO (C and D). Bar, 100 μm. (E) Quantification of cell migration expressed as fold of induction over unstimulated cells. Migration was enhanced in cells transfected with Mig6 siRNAs (gray bars) compared with GFP siRNAs (black bars) in the absence or presence of aphidicolin (Aphid.) (P = 0.019 and P < 0.0002, respectively, t test). *, P < 0.05; **, P < 0.01.

Mentions: Knock-down of Mig6 also enhanced MLP29 cell proliferation (unpublished data), as previously shown in EGF-stimulated fibroblasts (Xu et al., 2005). To separate Mig6's effects on cell proliferation from cell migration, we assayed cell migration in the presence of the cell cycle inhibitor, aphidicolin. In the presence of DMSO-containing control media, knock-down of Mig6 protein levels led to a significant increase in HGF-induced cell migration (Fig. 4, A, B, and E). This effect was not diminished by the presence of aphidicolin, if anything, it was enhanced slightly (Fig. 4, C–E). These data indicate that endogenous Mig6 blocks cell migration independently of its antiproliferative effects.


Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth.

Pante G, Thompson J, Lamballe F, Iwata T, Ferby I, Barr FA, Davies AM, Maina F, Klein R - J. Cell Biol. (2005)

Physiologic inhibition of HGF-mediated cell migration by Mig6 is independent of its effects on proliferation. Representative Hoechst dye–labeled MLP29 cells that were transfected with GFP-specific siRNAs (A and C) or Mig6-specific siRNAs (B and D) migrated onto the lower face of the Boyden chamber membrane upon stimulation with HGF. The cells were exposed to media containing DMSO (A and B) or 1.6 μg/ml aphidicolin solubilized in DMSO (C and D). Bar, 100 μm. (E) Quantification of cell migration expressed as fold of induction over unstimulated cells. Migration was enhanced in cells transfected with Mig6 siRNAs (gray bars) compared with GFP siRNAs (black bars) in the absence or presence of aphidicolin (Aphid.) (P = 0.019 and P < 0.0002, respectively, t test). *, P < 0.05; **, P < 0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171179&req=5

fig4: Physiologic inhibition of HGF-mediated cell migration by Mig6 is independent of its effects on proliferation. Representative Hoechst dye–labeled MLP29 cells that were transfected with GFP-specific siRNAs (A and C) or Mig6-specific siRNAs (B and D) migrated onto the lower face of the Boyden chamber membrane upon stimulation with HGF. The cells were exposed to media containing DMSO (A and B) or 1.6 μg/ml aphidicolin solubilized in DMSO (C and D). Bar, 100 μm. (E) Quantification of cell migration expressed as fold of induction over unstimulated cells. Migration was enhanced in cells transfected with Mig6 siRNAs (gray bars) compared with GFP siRNAs (black bars) in the absence or presence of aphidicolin (Aphid.) (P = 0.019 and P < 0.0002, respectively, t test). *, P < 0.05; **, P < 0.01.
Mentions: Knock-down of Mig6 also enhanced MLP29 cell proliferation (unpublished data), as previously shown in EGF-stimulated fibroblasts (Xu et al., 2005). To separate Mig6's effects on cell proliferation from cell migration, we assayed cell migration in the presence of the cell cycle inhibitor, aphidicolin. In the presence of DMSO-containing control media, knock-down of Mig6 protein levels led to a significant increase in HGF-induced cell migration (Fig. 4, A, B, and E). This effect was not diminished by the presence of aphidicolin, if anything, it was enhanced slightly (Fig. 4, C–E). These data indicate that endogenous Mig6 blocks cell migration independently of its antiproliferative effects.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, 82152 Munich-Martinsried, Germany.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus