ERBB receptor feedback inhibitor 1 (ERRFI1) (ERRFI1)

ERBB receptor feedback inhibitor 1 (ERRFI1), also known as Mitogen-inducible gene 6 (MIG6), is a cytoplasmic scaffold protein that acts as a potent negative regulator of the epidermal growth factor receptor (EGFR) family (UniProt: Q9UJM3; NCBI Gene: 54206). It functions by binding to the kinase domain of ERBB receptors, preventing their dimerization and activation, and facilitating their endocytosis and degradation (Zhang et al., Nature, 2007). In many cancers, ERRFI1 is downregulated or lost, leading to sustained oncogenic signaling through the EGFR/MAPK and PI3K/AKT pathways (Ferby et al., Nature Medicine, 2006). Consequently, ERRFI1 is considered a tumor suppressor, and its expression levels are frequently used as a biomarker to predict the efficacy of EGFR-targeted therapies (Balsara et al., Cancer Research, 2011). While there are currently no direct pharmacological activators of ERRFI1 in clinical use, research focuses on restoring its function or using its expression status to guide treatment with tyrosine kinase inhibitors (Park et al., Cancer Discovery, 2015). Its role extends beyond cancer to include regulation of skin homeostasis and glucose metabolism (GeneCards: ERRFI1). The mRNA levels of ERRFI1 are often measured to assess the EGFR addiction of tumors, where low levels correlate with resistance to certain inhibitors (Monast et al., Molecular Cancer Therapeutics, 2011).

Other names

Mitogen-inducible gene 6MIG6MIG-6Receptor-associated late transducerRALTGene 33

ERRFI1 acts as a negative feedback regulator by binding to the kinase domain of EGFR and other ERBB family members, which sterically inhibits the formation of the active asymmetric dimer and promotes receptor internalization and lysosomal degradation.