Inhibition of Cdc42 is essential for Mig-6 suppression of cell migration induced by EGF

Abstract

The adaptor protein Mig-6 is a negative regulator of EGF signaling. It is shown that Mig-6 inhibits cell migration via direct interaction with the ErbB receptors, thereby inhibiting cross-phosphorylation or targeting the receptors for degradation. Mig-6 has also been shown to bind to and inhibit the Rho GTPase Cdc42 to suppress cytoskeletal rearrangement. However, the molecular mechanism(s) by which Mig-6 inhibits cell migration via Cdc42 is still not entirely clear. Here, we show that Mig-6 binding to Cdc42 is necessary and sufficient to inhibit EGF-induced filopodia formation and migration. This binding, mediated by four specific residues (I11, R12, M26, R30) in the Mig-6 CRIB domain, is essential for Mig-6 function. In addition, ectopic expression of Cdc42 reverses Mig-6 inhibition of cell migration. Mig-6 CRIB domain, alone, is sufficient to inhibit cell migration. Conversely, Mig-6 binding to EGFR is dispensable for Mig-6-mediated inhibition of cell migration. Moreover, we found that decreased Mig-6 expression correlates with cancer progression in breast and prostate cancers. Together, our results demonstrate that Mig-6 inhibition of Cdc42 signaling is critical in Mig-6 function to suppress cell migration and that dysregulation of this pathway may play a critical role in cancer development.

Single-cell RNA sequencing reveals an altered gene expression pattern as a result of CRISPR/cas9-mediated deletion of Gene 33/Mig6 and chronic exposure to hexavalent chromium in human lung epithelial cells

“…Again, KO cells exhibited significantly quicker migration than the WT cells (Figure 4C). These results confirm the previous finding that Gene 33 negatively regulates cell migration (Pante et al , 2005; Jiang et al , 2016). Intriguingly however, Cr(VI) treatment alone had limited effect on cell migration under our experimental conditions (Figure 4).…”

“…Gene 33 has been shown to regulate cell migration and tumor metastasis (Pante et al , 2005; Jiang et al , 2016). We thus compared cell migration between KO (#22) and WT (#25) cells with or without Cr(VI) treatment using the scratch assay.…”

“…Gene 33 has also been shown to regulate the function of NF-κB (Tsunoda et al , 2002). Accumulating evidence has linked Gene 33 with tumor cell migration and metastasis, likely by regulating the EGFR and HGF/c-Met signaling pathways, and the small G protein CDC42 (Pante et al , 2005; Jiang et al , 2016). Our recent work showed that Gene 33 may also be involved in the DNA damage response and genomic instability induced by the genotoxic carcinogen hexavalent chromium [Cr(VI)] (Park et al , 2016).…”

Overexpression of Mig-6 in Limb Mesenchyme Leads to Accelerated Osteoarthritis in Mice

“…While Mig-6 had been identified as a negative regulator of EGFR signaling, it also interacts with a number of other potential candidate proteins that may contribute to the phenotype described here, such as Cdc42 (60), c-Abl (61), and the hepatocyte growth factor receptor c-Met (62). Therefore, additional work is necessary to elucidate the potential role of these proteins in the phenotype presented.…”

Overexpression of mig-6 in cartilage induces an osteoarthritis-like phenotype in mice

“…While the EGFR is the best characterized substrate of Mig-6, other substrates have been described. Mig-6 binds to different proteins such as the cell division control protein 42 homolog (Cdc42) (72), c-Abl (73), and the hepatocyte growth factor receptor c-Met (74). While we cannot exclude that deregulation of these other substrates contributes to the observed phenotypes, the similarities of defects in our mice with those seen upon cartilage-specific deletion of EGFR suggest that decreased EGFR signaling is the main cause for the advanced OA observed in our mutant mice.…”