MIG6, or Mitogen-Inducible Gene 6, is a protein that regulates cell growth and division. Cells receive signals to grow, multiply, or stop, and MIG6 helps maintain this balance. Understanding MIG6’s role advances knowledge about fundamental bodily functions and their relation to various diseases.
How MIG6 Controls Cell Growth
MIG6 primarily inhibits the Epidermal Growth Factor Receptor (EGFR) pathway. EGFR is a cell surface receptor that receives signals, such as epidermal growth factor (EGF), which tell the cell to grow and divide. When EGF binds to EGFR, it triggers events inside the cell that promote cell proliferation.
MIG6 functions as a “brake” for this pathway. It binds directly to the EGFR’s kinase domain, the part responsible for activating downstream signals. This binding prevents EGFR from sending uncontrolled growth signals, helping maintain normal cell division. The induction of MIG6 mRNA expression in response to EGF suggests a negative regulatory feedback loop. This means that as EGF stimulates growth, MIG6 production increases to counteract and limit that growth, ensuring cellular balance.
MIG6 and Cancer Development
Disruptions in MIG6’s normal function can contribute to cancer development. MIG6 is considered a tumor suppressor, meaning that when it functions correctly, it helps prevent the formation and growth of tumors.
When MIG6 expression is reduced, mutated, or its function is impaired, cells lose this “brake” on growth. This loss allows for uncontrolled cell proliferation, which is a hallmark of cancer. For example, mice with a germline disruption of Mig6 can develop epithelial hyperplasia, adenoma, and adenocarcinoma in organs such as the lung, gallbladder, and bile duct. Additionally, MIG6 is known to be silenced in many human epithelial cancers, including those of the lung, pancreas, breast, and skin.
Loss of MIG6 accelerates the initiation and progression of lung adenocarcinoma driven by mutant EGFR in mouse models. While MIG6 promotes the degradation of wild-type EGFR, it may not promote the degradation of mutant EGFR, allowing these mutant receptors to persist and drive tumor growth. This suggests that even when mutant EGFR is present, MIG6 still plays a role in delaying tumor development, highlighting its importance as a tumor suppressor.
MIG6 in Cancer Treatment and Research
MIG6’s role has implications for cancer treatment and research. MIG6 has potential as a biomarker, which is a measurable indicator that can help predict how patients might respond to certain therapies. This is particularly relevant for treatments that target EGFR. For instance, a higher ratio of EGFR to MIG6 expression has been observed in ALK TKI-treated and ALK TKI-resistant tumors, correlating with poor responsiveness to ALK/ROS1 inhibition in patient-derived cell lines.
Research efforts are exploring ways to restore MIG6 function or modulate its activity as a therapeutic approach. Downregulation of MIG6 has been found to be sustained following chronic exposure to ALK/ROS1 inhibitors, contributing to acquired resistance. This suggests that targeting MIG6 could be a strategy to overcome resistance to EGFR-tyrosine kinase inhibitors (TKIs) in lung cancer. Clinical data indicates that high MIG6 expression is associated with a poor prognosis in lung adenocarcinoma patients, with or without EGFR mutations.