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

Hepatocyte Growth Factor (HGF) is a pleiotropic factor acting on
cells expressing the Met receptor tyrosine kinase. HGF/Met
signaling has been described in detail and it is known to control
cell migration, growth and differentiation in several embryonic
organs and to be implicated in human cancer. Conversely, little is
known about the transcriptional targets that lead to Met-mediated
biological functions. Also, little is known about the physiological
mechanisms that attenuate Met signaling. This work provides the
results of a screen for genes transcriptionally regulated by Met in
several cell lines and addresses the functions of the highly
inducible gene Mig6 (Mitogen-inducible-gene6, also called Gene 33
and RALT). By the use of Met loss of function mutant mice Met is
shown to be the major inducer of mig6 in hepatocytes and lungs of
E13.5 embryos. Mig6 is shown in turn to negatively regulate
HGF/Met-induced cell migration. The effect is observed by Mig6
overexpression and reversed by Mig6 siRNA knock down experiments
indicating that endogenous Mig6 is part of a mechanism that
inhibits Met signaling. Mig6 functions in cells of hepatic origin
and in neurons suggesting a role for Mig6 in different cell
lineages. Mechanistically, Mig6 requires an intact Cdc42/Rho
interactive binding (CRIB) domain to exert its inhibitory action
suggesting that Mig6 acts at least in part distally from Met
possibly by sequestering Rho-like GTPases. Because Mig6 is also
induced by HGF stimulation, this work provides evidence that Mig6
is part of a negative feedback loop that attenuates Met functions
in different contexts and cell types.