Mig6 is a negative regulator of EGF receptor–mediated skin morphogenesis and tumor formation

Abstract

The growing number of recently identified negative feedback regulators of receptor tyrosine kinases (RTKs) highlights the importance of signal attenuation and modulation for correct signaling outcome. Mitogen-inducible gene 6 (Mig6 also known as RALT or Gene 33) is a multiadaptor protein thought to be involved in the regulation of RTK and stress signaling. Here, we show that deletion of the mouse gene encoding Mig6 (designated Errfi1, which stands for ERBB receptor feedback inhibitor 1) causes hyperactivation of endogenous epidermal growth factor receptor (EGFR) and sustained signaling through the mitogen-activated protein kinase (MAPK) pathway, resulting in overproliferation and impaired differentiation of epidermal keratinocytes. Furthermore, Errfi1-/- mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced formation of skin tumors. A tumor-suppressive role for Mig6 is supported by our finding that MIG6 is downregulated in various human cancers. Inhibition of endogenous Egfr signaling with the Egfr inhibitor gefitinib (Iressa) or replacement of wild-type Egfr with the kinase-deficient protein encoded by the hypomorphic Egfr(wa2) allele completely rescued skin defects in Erffi1-/- mice. Carcinogen-induced tumors displayed by Errfi1-/- mice were highly sensitive to gefitinib. These results indicate that Mig6 is a specific negative regulator of Egfr signaling in skin morphogenesis and is a novel tumor suppressor of Egfr-dependent carcinogenesis.

Evidence that MIG-6 is a tumor-suppressor gene

“…Likewise, Mig-6 may also function as a tumor-suppressor in other organs, since animals with a Mig-6 deficiency also develop gallbladder and bile duct cancers ( Figure 5 and Table 3). Very recently, another group also reported that Mig-6 deficiency in mice caused skin cancer in addition to the joint phenotype that we have previously reported (Zhang et al, 2005;Ferby et al, 2006). Moreover, it has recently been reported that MIG-6 expression is lost in ErbB2-amplified breast carcinomas (Anastasi et al, 2005).…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Consistent with its proposed role in negatively regulating EGFR, mutation of LRIG-1 (LIG-1) in mice leads to psoriasiform skin lesions consistent with the proposed role of EGFR in psoriasis [104,105]. Notably, Mig-6 mouse mutants hyperactivate EGFR, leading to MAPK stimulation and the development of benign and malignant tumors of the stomach, colon, biliary tree and lung with enhanced susceptibility to carcinogen-induced skin cancer [106,107]. Mig-6 has also been found to be mutated in nonsmall cell lung cancer (NSCLC) cell lines and rarely in primary lung cancer, suggesting that MIG-6 may also play a role as a tumor suppressor gene in humans [107].…”

Signaling networks assembled by oncogenic EGFR and c-Met

“…We observed Spry1 (Y53), Spry2 (Y55), and Spry4 (Y75) in H3255 and HCC827 cells but not other cell lines (SI Table 3). Mig6 has been reported to be a negative regulator of EGFR and may function as a tumor suppressor (20). Mig6 is tyrosine phosphorylated at Y394 in mutant EGFR cell lines (SI Table 3 and SI Fig.…”