We identified MIG6 (gene symbol ERRFI1) as a phosphorylation target of mutant EGFRs in our mass spectrometry-based experiments. MIG6, also known as ERBB receptor feedback inhibitor 1 (ERRFI1) and receptor-associated late transducer (RALT), is a scaffolding adaptor protein whose expression is rapidly induced by a variety of growth factors (including EGF) and by hormones and other stressors. MIG6 negatively regulates EGFR, ERBB2, and several other receptor tyrosine kinases and their signaling pathways. We hypothesized that loss of MIG6 may cooperate with mutant EGFR to induce lung tumorigenesis. To test this hypothesis we crossed doxycycline inducible mutant EGFR transgenic mice with Mig6 null mice. Upon doxycycline induction of mutant EGFRs that are expressed in type II epithelial cells, lung tumorigenesis is indeed accelerated upon loss of Mig6 expression. We have completed the survival curve upon doxycycline induction of mutant EGFRs in wild type, heterozygous and knock-out mice. We convincingly show that tumorigenesis is accelerated in Mig6 null background suggesting that Mig6 is indeed a tumor suppressor in mutant EGFR-induced lung tumorigenesis. We have completed the evaluation of histology of mouse lung tumor in various genotypes in collaboration with Dr. Ilona Linnoila. We have also initiated a collaboration with Dr. Mark Simpson to quantify immunohistochemical staining of various targets in these tumors. We are currently performing biochemical experiments to elucidate the functional role of increased tyrosine phosphorylation at Y394 and Y395 of ERRFI1.We have also initiated a collaboration with Dr. Debbie Morrison in the NCI intramural program to understand the biochemical implication of Mig6 phosphorylation and interaction with EGFR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011412-02
Application #
8553165
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2012
Total Cost
$369,851
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Maity, Tapan K; Venugopalan, Abhilash; Linnoila, Ilona et al. (2015) Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor-Driven Lung Adenocarcinoma. Cancer Discov 5:534-49