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

Abstract

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