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This is a protein complex formed from Mitogen-Inducible Gene 6 Protein (Mig-6) and Epidermal Growth Factor Receptor (EGFR)4. Mig-6 complexes with and inhibits EGFR. Mig-6 contains a protein domain that can interact with the EGFR protein family4. EGFR catalyzes the phosphorylation of Mig-6 when the two proteins form a complex, and when this occurs, Mig-6 changes its structure and irreversibly inhibits the EGFR4.

Function

EGFR plays a role in the metastasization and development of carcinomas, because it contributes to growth in epithelial tissue.The irreversible inhibition EGFR by Mig-6 will, in people with cancer, prevent the cancer from growing and progressing further. Therefore, Mig-6 regulates the activities of EGFR, so that growth does not get out of control.

Disease

The Mig-6/EGFR protein complex has great importance to the prevention and suppression of epithelial tumors. Since EGFR promotes epithelial growth, and therefore the growth of epithelial cancers when they occur, the Mig-6/EGFR complex is essentially a tumor suppressing complex, because Mig-6 inhibits the function of EGFR

Relevance

Mig-6 is a feedback inhibitor that binds, inhibits, and drives internalization of ErbB-family receptors. Mig-6 inactivates the EGFR and thus is critical in better understanding human cancers2. EGFR phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.

Somatic mutations in the EGFR kinase domain have been shown to drive lung adenocarcinoma, a specific type of lung cancer. Mig-6 is a target for phosphorylation by mutant EGFR’s and is a promising tumor suppressor for mutant-driven lung adenocarcinoma. During a research study, lung tumor formation progressed faster in mice lacking Mig-62. Interaction between Mig-6 and EGFR, stabilizes EGFR, inhibiting mutant EGFR, and preventing or delaying further growth of mutant EGFR-driven tumors.

Studies have shown that there is a relationship between the deletion of the Mig-6 gene and the formation of certain types of gliomas.5 In addition, deletion of the Mig6-encoding gene in mice has been shown to hyperactivate EGFR signaling, leading to skin hyperplasia, a condition affecting the sebaceous glands, and tumor formation in skin, the lungs and other epithelial tissues.

Structural highlights

Global Symmetry: Asymmetric - C12 Global Stoichiometry: Hetero 2-mer - AB2

The domain structure of Mig6 includes an N-terminal CRIB domain, a motif that mediates association with the Rho-family GTPase Cdc42 and a C-terminal ErbB-binding region, which is necessary and sufficient for binding and inhibition of EGFR7. In the Mig6-YpY structure, the kinase adopts an active conformation, and the Mig6 peptide interacts with the activation loop in an antiparallel manner.