Affinage

ERRFI1

ERBB receptor feedback inhibitor 1 · UniProt Q9UJM3

Length
462 aa
Mass
50.6 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERRFI1 (also known as MIG-6/RALT/Gene 33) is a stress-inducible, multifunctional adaptor protein that serves as a central feedback inhibitor of ErbB receptor tyrosine kinase signaling while also integrating cytoskeletal, DNA damage, and metabolic pathways. Its conserved ErbB-binding region (EBR) directly suppresses EGFR kinase activity by engaging the αI-helix allosteric site, while a separate domain drives EGFR endocytosis and lysosomal degradation through interactions with AP-2, Intersectins, and the SNARE protein STX8, thereby achieving durable signal extinction (PMID:17599051, PMID:20421427, PMID:20351267). Independent of EGFR binding, ERRFI1 inhibits Cdc42-dependent cell migration via its CRIB domain, negatively regulates STAT3 and AKT phosphorylation through direct protein–protein interactions, and promotes ATM-dependent DNA damage responses from the nucleus (PMID:27341132, PMID:28925396, PMID:29843645, PMID:28842482). ERRFI1 itself is transcriptionally induced by the Ras–Raf–ERK pathway and by progesterone receptor signaling, is subject to proteasomal degradation, and is phosphorylated by Chk1 at Ser251 to attenuate its inhibitory function, establishing multilayered feedback control; loss of ERRFI1 in mice causes degenerative joint disease, endometrial hyperplasia and cancer, and enhanced ErbB-driven proliferation (PMID:12226756, PMID:22505024, PMID:16087873, PMID:19439667).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    Establishing ERRFI1 as a direct ErbB-2/EGFR-interacting inhibitor and Cdc42 effector resolved the dual question of how an immediate-early gene product feeds back on receptor signaling and connects to Rho-family GTPase pathways.

    Evidence Yeast two-hybrid, Co-IP, GST pulldown identifying ErbB-2 and Cdc42 as binding partners, with proliferation/transformation assays and SAPK/JNK activation

    PMID:10749885 PMID:11003669

    Open questions at the time
    • Structural basis of ERRFI1–ErbB-2 interaction unknown
    • Whether Cdc42 binding and ErbB binding are functionally coupled was not tested
    • Endogenous stoichiometry not determined
  2. 2001 High

    Demonstrating that Mig-6 binds EGFR in a kinase-activity-dependent manner and enhances EGFR internalization established it as a pan-ErbB feedback inhibitor that operates both at the kinase level and at receptor trafficking.

    Evidence Yeast two-hybrid with EGFR kinase domain, Co-IP, receptor internalization and transformation assays

    PMID:11843178

    Open questions at the time
    • Mechanism of enhanced internalization not dissected
    • ErbB-3/ErbB-4 binding not yet tested
  3. 2002 High

    Showing that ERRFI1 is transcriptionally induced by the Ras–Raf–ERK pathway and degraded by the proteasome established the complete negative-feedback loop architecture: ERK induces ERRFI1, which then suppresses ErbB–ERK signaling and is itself cleared by ubiquitination.

    Evidence Pharmacological ERK inhibition, inducible Raf:ER chimera, ubiquitin Co-IP, proteasome inhibitor treatment

    PMID:12226756

    Open questions at the time
    • E3 ubiquitin ligase responsible for ERRFI1 degradation not identified
    • Half-life quantification not performed
  4. 2002 Medium

    Discovery that a proteolytically processed CRIB-containing fragment of Mig-6 activates NF-κB by competing with NF-κB for IκBα binding revealed a non-ErbB signaling function downstream of limited proteolysis.

    Evidence Luciferase reporter, Co-IP of CRIB fragment with IκBα, CRIB deletion and S38A mutants

    PMID:12384522

    Open questions at the time
    • Protease responsible for Mig-6 cleavage not identified
    • Physiological relevance of NF-κB activation not confirmed in vivo
    • Not independently replicated
  5. 2003 High

    Extending ERRFI1 inhibition to ErbB-4 and ErbB-2:ErbB-3 heterodimers, and showing that an EBR-deletion mutant loses receptor-proximal but retains partial receptor-distal suppression, dissected the architecture of ERRFI1's inhibitory mechanism into two functional layers.

    Evidence Co-IP with multiple ErbB family members, ERK/AKT phosphorylation assays, RALT-ΔEBR mutant

    PMID:12833145

    Open questions at the time
    • Identity of the receptor-distal suppressive mechanism unknown
    • Quantitative contribution of each layer not measured
  6. 2004 High

    Demonstrating that the EBR domain is necessary and sufficient to block EGFR autophosphorylation in vitro and that dexamethasone-induced ERRFI1 mediates glucocorticoid suppression of EGF signaling linked hormonal regulation to ERRFI1's kinase-inhibitory function.

    Evidence In vitro EGFR autophosphorylation assay, domain deletions, RNAi reversal of dexamethasone effect

    PMID:15556944

    Open questions at the time
    • Glucocorticoid receptor binding site in ERRFI1 promoter not mapped
    • Whether glucocorticoid–ERRFI1 axis operates in all tissues not tested
  7. 2005 High

    In vivo gain-of-function (K14-RALT transgene producing Waved-like phenotype) and loss-of-function (Mig-6 knockout causing degenerative joint disease) in mice validated ERRFI1 as a physiologically essential EGFR inhibitor in skin and cartilage homeostasis.

    Evidence Transgenic mouse with dose-dependent phenotype; germline KO mouse with joint degeneration; Rag2 double-KO epistasis excluding immune involvement

    PMID:16007071 PMID:16087873

    Open questions at the time
    • Molecular events downstream of EGFR hyperactivation in chondrocytes not detailed
    • Whether joint phenotype is solely EGFR-dependent not formally tested
  8. 2007 High

    Mapping the EBR–EGFR interaction to the αI-helix (953RYLVIQ958) allosteric site provided a structural mechanism: ERRFI1 locks EGFR in an inactive conformation by blocking the asymmetric dimer interface.

    Evidence In vitro kinase assay, EBR peptide binding, site-directed mutagenesis of αI-helix residues

    PMID:17599051

    Open questions at the time
    • No crystal structure of the ERRFI1-EBR:EGFR complex at this time
    • Whether this mechanism applies equally to all ErbB family members not tested
  9. 2009 High

    Placing ERRFI1 downstream of progesterone receptor–SRC-1 signaling and showing that Mig-6-deficient mice develop estrogen-driven endometrial adenocarcinoma revealed ERRFI1 as a hormone-regulated tumor suppressor in the uterus.

    Evidence Germline KO mouse with ovariectomy/hormone treatment, endometrial adenocarcinoma development

    PMID:19439667

    Open questions at the time
    • Direct transcriptional regulation of ERRFI1 by PR not shown at the promoter level
    • Whether human endometrial cancer recapitulates this mechanism not established
  10. 2010 High

    Identification of AP-2, Intersectin, and STX8 as ERRFI1 binding partners that mediate EGFR endocytosis and late-endosome/lysosomal sorting established a bipartite mechanism: one domain suppresses kinase activity, a separate domain ensures receptor destruction.

    Evidence Co-IP with AP-2, Intersectins, and STX8; EGFR trafficking and degradation assays; rescue of endocytosis-defective EGFR mutants

    PMID:20351267 PMID:20421427

    Open questions at the time
    • Precise ERRFI1 residues mediating AP-2 and STX8 binding not mapped
    • Whether ERRFI1-driven endocytosis operates independently of Cbl-mediated ubiquitination not resolved
  11. 2012 High

    Discovery that Chk1 phosphorylates ERRFI1 at Ser251 to attenuate its EGFR-inhibitory activity uncovered a mechanism by which DNA damage checkpoint signaling cross-talks with receptor tyrosine kinase output, converting ERRFI1 from an active inhibitor to an inactive form.

    Evidence In vitro kinase assay, MS phosphosite mapping, S251A mutagenesis, RNAi epistasis (Chk1 + Mig-6 co-depletion rescue)

    PMID:22505024

    Open questions at the time
    • Phosphatase that reverses Ser251 phosphorylation not identified
    • Whether other kinases also regulate ERRFI1 function not tested
  12. 2014 High

    Cartilage-specific deletion of Mig-6 confirmed that ERRFI1 acts cell-autonomously in chondrocytes to restrain EGFR-driven proliferation and protect against osteoarthritis-like degeneration.

    Evidence Col2a1-Cre conditional KO mouse, EGFR phosphorylation immunostaining, chondrocyte proliferation assays

    PMID:24550287

    Open questions at the time
    • Specific EGFR ligand driving joint pathology not identified
    • Therapeutic rescue by ERRFI1 restoration not attempted
  13. 2017 High

    Dissecting ERRFI1's CRIB domain showed that Cdc42 binding (via I11, R12, M26, R30) is necessary and sufficient to inhibit filopodia formation and cell migration, independently of EGFR binding, formally separating the cytoskeletal and receptor-inhibitory functions of the protein.

    Evidence CRIB point mutagenesis, Co-IP with Cdc42, migration and filopodia assays, domain rescue experiments

    PMID:27341132

    Open questions at the time
    • Whether CRIB–Cdc42 interaction also affects polarity or invasion not tested
    • In vivo relevance of CRIB-mediated migration inhibition not established
  14. 2017 High

    Demonstrating direct MIG-6–STAT3 interaction and showing that epithelial-specific Mig-6 loss causes endometrial hyperplasia with aberrant STAT3 phosphorylation extended ERRFI1's inhibitory reach beyond receptor kinases to a transcription factor, providing a new mechanism for its tumor-suppressive activity in the uterus.

    Evidence Conditional epithelial KO mouse, immunoprecipitation, STAT3 phosphorylation assay

    PMID:28925396

    Open questions at the time
    • Binding interface between MIG-6 and STAT3 not mapped
    • Whether STAT3 inhibition is direct or requires an intermediate not resolved
  15. 2017 Medium

    Finding that ERRFI1 localizes to chromatin and promotes ATM–H2AX interaction without inducing DNA damage revealed a nuclear scaffolding function that places ERRFI1 in DNA damage response signaling independent of its cytoplasmic ErbB-inhibitory role.

    Evidence Subcellular fractionation, Co-IP with H2AX and ATM, domain mutagenesis, ATM pharmacological inhibition

    PMID:28842482

    Open questions at the time
    • Not independently replicated
    • Whether nuclear ERRFI1 function is physiologically relevant in DNA repair outcomes not tested
    • ATM dependence shown only pharmacologically
  16. 2018 Medium

    Revealing that ERRFI1 has a context-dependent dual role in AKT regulation — inhibiting AKT via EGFR in EGFR-high cells but promoting AKT by disrupting the PHLPP–AKT interaction in EGFR-low cells — explained contradictory reports and established ERRFI1 as a context-dependent signaling switch.

    Evidence Co-IP of ERRFI1 with PHLPP and AKT, knockdown/overexpression in EGFR-high versus EGFR-low cell lines

    PMID:29335246

    Open questions at the time
    • Structural basis of PHLPP displacement not determined
    • Threshold of EGFR expression for mode-switching not defined
    • Not replicated by independent laboratory
  17. 2021 Medium

    Discovery that MIG-6 recruits the HAUSP deubiquitinase to stabilize HIF1α and drive glycolytic reprogramming in triple-negative breast cancer revealed a pro-tumorigenic function that contrasts with ERRFI1's canonical tumor-suppressive role.

    Evidence Co-IP of MIG-6 with HAUSP, HIF1α stability assay, metabolic profiling, mouse xenograft

    PMID:33655623

    Open questions at the time
    • Whether HAUSP recruitment is ErbB-dependent not tested
    • Generalizability beyond triple-negative breast cancer unknown
    • Not independently replicated
  18. 2022 High

    Genetic epistasis showing that Erbb2 ablation fully rescues all phenotypes of Mig-6-deficient endometrium (infertility, hyperplasia, progesterone resistance) placed ERBB2 overexpression as the principal effector downstream of ERRFI1 loss in the uterus.

    Evidence Double conditional KO mouse (Mig-6d/d Erbb2d/d), fertility and implantation assays, transcriptomics

    PMID:35232969

    Open questions at the time
    • Whether ERRFI1 directly degrades ERBB2 protein or merely restrains its signaling not distinguished
    • Whether ERBB2 is the sole relevant ErbB target in all endometrial contexts unclear
  19. 2024 Medium

    Identification of GRB2 stabilization by ERRFI1 (hindering proteasomal degradation) and its role in promoting hepatocyte apoptosis and ferroptosis during ischemia–reperfusion injury added a new cell-death axis to ERRFI1's functional repertoire.

    Evidence Hepatocyte-specific KO mouse, Co-IP of ERRFI1–GRB2, proteasomal degradation assay, GRB2 overexpression rescue

    PMID:38862918

    Open questions at the time
    • Whether GRB2 stabilization depends on the EBR domain not tested
    • Ferroptosis mechanism downstream of GRB2 not elucidated
    • Not independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ligase that ubiquitinates ERRFI1, the structural basis of the full-length ERRFI1–EGFR complex, how nuclear versus cytoplasmic ERRFI1 pools are partitioned and regulated, and whether the pro-tumorigenic HAUSP/HIF1α-stabilizing function and the anti-tumorigenic ErbB-inhibitory function coexist or are mutually exclusive in specific cancer contexts.
  • E3 ligase for ERRFI1 ubiquitination not identified
  • Full-length ERRFI1 crystal structure unavailable
  • Nuclear–cytoplasmic partitioning regulation not systematically studied

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005829 cytosol 4 GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1643685 Disease 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9609507 Protein localization 2
Partners
AKT1CDC42EGFRERBB2GRB2PHLPP1STAT3STX8

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 RALT (ERRFI1/Gene 33) was identified as an ErbB-2-interacting protein via yeast two-hybrid screen; the interaction requires active ErbB-2 catalytic function (but not autophosphorylation), is mediated by residues 282–395 of RALT, and results in inhibition of ErbB-2-driven cell proliferation, transformation, and sustained ERK1/2 activation. RALT was also found to associate with GRB2 in living cells. Yeast two-hybrid, GST pulldown, Co-IP, cell proliferation and transformation assays Molecular and cellular biology High 11003669
2001 Mig-6 (ERRFI1) was identified in a yeast two-hybrid screen with the EGFR kinase domain; upon EGF stimulation Mig-6 binds to EGFR via an acidic region (aa 985–995) in a kinase-activity-dependent manner, overexpression reduces EGF-induced ERK2 activation and enhances EGFR internalization, and Mig-6 inhibits EGFR-overexpression-induced transformation. Yeast two-hybrid, Co-IP, ERK2 activation assay, receptor internalization assay, transformation assay Biological chemistry High 11843178
2000 Gene 33/Mig-6 interacts in vivo and in a GTP-dependent manner in vitro with Cdc42Hs (a Rho-family GTPase), and transient expression of Gene 33 selectively activates SAPK/JNK kinases. Co-IP in vivo, in vitro GTP-dependent pulldown, SAPK/JNK activation assay The Journal of biological chemistry High 10749885
2003 RALT/ERRFI1 binds ligand-activated EGFR, ErbB-4, and ErbB-2:ErbB-3 dimers, functioning as a pan-ErbB inhibitor; a mutant (RALT deltaEBR) unable to bind ErbB RTKs loses the ability to suppress ERK and AKT activation at saturating ligand concentrations, demonstrating that suppressive activity is primarily receptor-proximal. RALT deltaEBR retains partial suppression of ErbB-2:ErbB-3 mitogenic signals at a receptor-distal level. Co-IP, cell proliferation assays, ERK and AKT phosphorylation assays, mutant analysis Oncogene High 12833145
2002 RALT/ERRFI1 protein is ubiquitinated and degraded by the proteasome; its expression is driven transcriptionally through the Ras-Raf-ERK pathway (pharmacological ERK inhibition blocks RALT induction; activated Raf:ER chimera is sufficient to induce RALT), providing integrated transcriptional and post-translational control. Ubiquitin Co-IP, proteasome inhibitor treatment, pharmacological kinase inhibitors, inducible Raf:ER system Oncogene High 12226756
2004 Gene 33/ERRFI1 inhibits EGFR autophosphorylation and downstream activation of Ras, ERK, JNK, Akt/PKB, and Rb; the Ack-homology (EBR) domain is necessary and sufficient for this inhibition. Dexamethasone-induced Gene 33 expression mediates glucocorticoid suppression of EGF signaling, as demonstrated by RNA interference reversal. In vitro EGFR autophosphorylation assay, domain deletion mutants, RNAi knockdown, Western blot The Journal of biological chemistry High 15556944
2007 The evolutionarily conserved ErbB-binding region (EBR) of RALT/MIG6 is necessary and sufficient to suppress EGFR kinase catalytic activity in vitro and in intact cells; the mechanism involves binding of the EBR to the 953RYLVIQ958 sequence in the αI helix of the EGFR kinase domain, which participates in allosteric control of EGFR activity. In vitro kinase assay, domain mutant overexpression, EBR peptide binding, site-directed mutagenesis Oncogene High 17599051
2010 RALT/MIG6 mediates EGFR endocytosis and lysosomal degradation via a domain distinct from the EGFR kinase-suppressive domain; RALT drives EGFR endocytosis by binding to AP-2 and Intersectins, rescues endocytic deficits of EGFR mutants (Dc214 and Y1045F), integrating kinase suppression with receptor removal for durable repression of EGFR signaling. Co-IP (RALT with AP-2 and Intersectins), endocytosis assays with EGFR mutants, lysosomal degradation assays, domain mutant analysis The Journal of cell biology High 20421427
2010 Mig-6 drives EGFR into late endosomes and lysosome-mediated degradation upon ligand stimulation by binding to the SNARE protein STX8 (required for late endosome trafficking), physically linking EGFR to STX8 during ligand-stimulated receptor trafficking. Co-IP (Mig-6 with STX8 and EGFR), EGFR trafficking assay, late endosome/lysosome localization Proceedings of the National Academy of Sciences of the United States of America High 20351267
2002 Full-length Mig-6 (but not CRIB domain-deleted Mig-6 or uncleavable Mig-6-S38A mutant) activates NF-κB transcription; Mig-6 undergoes limited proteolytic cleavage, and the processed N-terminal CRIB-containing fragment binds IκBα through its NF-κB binding region, competing with NF-κB for IκBα and releasing NF-κB. Luciferase reporter assay, Co-IP of CRIB fragment with IκBα, mutagenesis (CRIB deletion, S38A mutant) Cancer research Medium 12384522
2005 Targeted expression of RALT/MIG6 in mouse skin (K14-RALT transgene) generates a dose-dependent Waved-like phenotype (wavy coat, curly whiskers, open eyes at birth) due to suppression of EGFR signaling; ex vivo keratinocytes show reduced ErbB-ligand-induced responses, and RNAi knockdown of RALT enhances ErbB mitogenic signaling. Transgenic mouse (K14-RALT), ex vivo keratinocyte stimulation assays, RNAi knockdown EMBO reports High 16007071
2005 Targeted disruption of Mig-6 (ERRFI1) in mice leads to early onset degenerative joint disease with articular cartilage degradation and osteophyte formation; absence of Rag2 does not rescue the phenotype, excluding the acquired immune system. Mig-6 knockout chondrocytes show enhanced EGFR signaling and excessive proliferation. Germline knockout mouse, histology, Rag2 double-knockout epistasis Proceedings of the National Academy of Sciences of the United States of America High 16087873
2006 Gene 33/ERRFI1 is induced in cardiomyocytes by hypoxia; adenoviral overexpression promotes cardiomyocyte death by reducing Akt and ERK signaling, and RNAi knockdown of endogenous Gene 33 reduces hypoxia-induced cardiomyocyte death, demonstrating that Gene 33 is a pro-death component in ischemic injury. Adenoviral overexpression, RNAi knockdown, Akt/ERK phosphorylation assay, cardiomyocyte death assay Molecular and cellular biology High 16782890
2009 Mig-6 (ERRFI1) is a downstream target of progesterone receptor (PR) and SRC-1 in the uterus; absence of Mig-6 prevents progesterone from inhibiting estrogen-induced uterine responses, and ovariectomized Mig-6-deficient mice treated with estrogen develop endometrial adenocarcinoma, placing Mig-6 in a PR–SRC-1–Mig-6 pathway that suppresses endometrial cancer. Germline knockout mouse, ovariectomy/hormone treatment, uterine weight assay, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 19439667
2012 Chk1 kinase phosphorylates Mig-6 at Ser251 in vivo and in vitro; EGF stimulation promotes this phosphorylation via PI3K–Chk1 axis; the Ser251Ala substitution increases Mig-6 inhibitory activity against EGFR; Chk1 depletion inhibits EGF-dependent EGFR activation and cell growth, which is rescued by co-depletion of Mig-6, placing Chk1 as a positive regulator of EGFR signaling through Mig-6 inactivation. In vitro kinase assay, mass spectrometry phosphosite mapping, site-directed mutagenesis, RNAi epistasis, EGFR activation assay The EMBO journal High 22505024
2017 Mig-6 inhibits EGF-induced cell migration via its CRIB domain binding to Cdc42; four specific CRIB residues (I11, R12, M26, R30) mediate Cdc42 binding, which is necessary and sufficient to inhibit filopodia formation and migration. The CRIB domain alone is sufficient to inhibit migration; Mig-6 binding to EGFR is dispensable for this anti-migratory function. Co-IP, site-directed mutagenesis of CRIB domain, cell migration assay, filopodia formation assay, domain rescue experiments Oncotarget High 27341132
2017 MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells through protein–protein interaction; Mig-6 epithelial-specific knockout mice develop endometrial hyperplasia with aberrant STAT3 phosphorylation, and immunoprecipitation confirmed MIG-6–STAT3 interaction. Conditional epithelial-specific KO mouse, immunoprecipitation, STAT3 phosphorylation assay Oncogene High 28925396
2017 Gene 33/Mig-6 localizes to the nucleus and chromatin fractions; nuclear localization is regulated by its 14-3-3-binding domain; chromatin association is partially dependent on its ErbB-binding domain. Nuclear Gene 33 promotes ATM-dependent DNA damage response (DDR), associates with histone H2AX, and promotes ATM–H2AX interaction without triggering DNA damage. Gene 33 may regulate c-Abl targeting to chromatin. Subcellular fractionation, Co-IP (Gene 33 with H2AX and ATM), domain mutagenesis, ectopic expression with ATM inhibition The Journal of biological chemistry Medium 28842482
2018 ERRFI1 has a dual role in AKT regulation: in EGFR-high cells, ERRFI1 inhibits AKT signaling through EGFR inhibition; in EGFR-low cells, ERRFI1 positively modulates AKT signaling by interfering with the interaction between the inactivating phosphatase PHLPP and AKT, thereby promoting AKT activity. Co-IP (ERRFI1 with PHLPP and AKT), knockdown/overexpression, AKT phosphorylation assay, proliferation assay EMBO reports Medium 29335246
2010 Co-immunoprecipitation identified ERK2 as an MIG-6 interacting protein; Mig-6 ablation (alone or combined with Pten ablation) increases ERK2 phosphorylation, and Mig-6 loss promotes endometrial tumorigenesis partly through upregulation of apoptotic inhibitor Birc1. Co-IP, conditional double KO mouse, Western blot for phospho-ERK2 Oncogene Medium 20418913
2021 MIG-6 recruits HAUSP (USP7) deubiquitinase to stabilize HIF1α protein, leading to upregulation of GLUT1 and other HIF1α-regulated glycolytic genes in triple-negative breast cancer, thereby driving metabolic reprogramming toward glycolysis. Co-IP (MIG-6 with HAUSP), HIF1α protein stability assay, GLUT1 expression assay, metabolic array, mouse tumor xenograft EMBO reports Medium 33655623
2021 ERRFI1 induces apoptosis in hepatocellular carcinoma cells by binding PDCD2; PDCD2 knockdown decreases ERRFI1-induced apoptosis, establishing PDCD2 as a functional effector of ERRFI1-mediated apoptosis. Co-IP (ERRFI1 with PDCD2), RNAi knockdown, apoptosis assay Cell death discovery Medium 34608122
2022 Loss of MIG-6 in the endometrium causes ERBB2 overexpression and endometrial progesterone resistance; genetic ablation of Erbb2 in Mig-6 knockout mice rescues all Mig-6d/d phenotypes (non-receptive endometrium, infertility, hyperplasia), placing ERBB2 downstream of MIG-6 loss. Double conditional KO mouse (Mig-6d/dErbb2d/d), transcriptomics, fertility/implantation assays Nature communications High 35232969
2024 ERRFI1 interacts with GRB2 and maintains GRB2 stability by hindering its proteasomal degradation; hepatocyte-specific ERRFI1 knockout reduces apoptosis and ferroptosis in hepatic ischemia–reperfusion injury, and GRB2 overexpression reverses the protective effects of ERRFI1 silencing. Hepatocyte-specific KO mouse, Co-IP (ERRFI1–GRB2), proteasomal degradation assay, apoptosis and ferroptosis assays Molecular medicine (Cambridge, Mass.) Medium 38862918
2020 ANRIL lncRNA binds EZH2 and maintains H3K27me3 at the ERRFI1 promoter, epigenetically repressing ERRFI1 expression in cholangiocarcinoma; ANRIL knockdown increases ERRFI1 and inhibits tumor growth. RNA-seq after ANRIL knockdown, ChIP for H3K27me3 at ERRFI1 promoter, Co-IP (ANRIL-EZH2), in vitro and in vivo tumor assays Cancer science Medium 32378752
2018 In MET-TKI-resistant cancer cells, epigenetically induced miR-205 downregulates ERRFI1, which in turn causes EGFR activation and sustains resistance; anti-miR-205 reverts crizotinib resistance in vivo, and this mechanism operates in the absence of EGFR genetic alterations. miRNA profiling, RNA-seq, anti-miR-205 transduction, in vivo xenograft, patient sample analysis EMBO molecular medicine Medium 30021798
2014 Cartilage-specific deletion of Mig-6 in chondrocytes (Col2a1-Cre) causes excessive articular chondrocyte proliferation and an OA-like phenotype in knees (but not all joints affected in full KO), demonstrating that Mig-6 in chondrocytes regulates EGF receptor signaling and chondrocyte proliferation in joint homeostasis. Cartilage-specific conditional KO mouse, histology, EGFR phosphorylation immunostaining, proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 24550287
2018 MIG-6 interacts with AKT and inhibits AKT phosphorylation in uterine epithelial cells; in vitro studies revealed a direct MIG-6–AKT protein interaction, and Mig-6 epithelial-specific KO mice develop endometrial hyperplasia with increased phospho-AKT. Co-IP (MIG-6 with AKT), conditional epithelial KO mouse, AKT phosphorylation assay BMC cancer Medium 29843645

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Mig-6 is a negative regulator of the epidermal growth factor receptor signal. Biological chemistry 130 11843178
2000 Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Molecular and cellular biology 121 11003669
2000 Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. The Journal of biological chemistry 114 10749885
2006 Evidence that MIG-6 is a tumor-suppressor gene. Oncogene 109 16819504
2003 Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 101 12833145
2010 Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proceedings of the National Academy of Sciences of the United States of America 99 20351267
2010 A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation. The Journal of cell biology 96 20421427
2005 Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin. Oncogene 93 15856022
2004 Gene 33 is an endogenous inhibitor of epidermal growth factor (EGF) receptor signaling and mediates dexamethasone-induced suppression of EGF function. The Journal of biological chemistry 91 15556944
2010 Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes. Oncotarget 84 21113414
2009 Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease. Proceedings of the National Academy of Sciences of the United States of America 80 19439667
2007 Mig-6, signal transduction, stress response and cancer. Cell cycle (Georgetown, Tex.) 76 17351343
2002 Mitogen-inducible gene 6 (MIG-6), adipophilin and tuftelin are inducible by hypoxia. FEBS letters 76 12387890
2005 Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease. Proceedings of the National Academy of Sciences of the United States of America 75 16087873
2001 Induction of the SAPK activator MIG-6 by the alkylating agent methyl methanesulfonate. Molecular carcinogenesis 68 11429782
2002 Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control. Oncogene 66 12226756
2007 The evolutionarily conserved EBR module of RALT/MIG6 mediates suppression of the EGFR catalytic activity. Oncogene 65 17599051
1995 Identification of a novel mitogen-inducible gene (mig-6): regulation during G1 progression and differentiation. Experimental cell research 60 7641805
2010 The synergistic effect of Mig-6 and Pten ablation on endometrial cancer development and progression. Oncogene 54 20418913
1988 Reciprocal regulation of gene transcription by insulin. Inhibition of the phosphoenolpyruvate carboxykinase gene and stimulation of gene 33 in a single cell type. The Journal of biological chemistry 54 2843505
2009 C. elegans mig-6 encodes papilin isoforms that affect distinct aspects of DTC migration, and interacts genetically with mig-17 and collagen IV. Development (Cambridge, England) 53 19297413
2018 Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation. EMBO reports 51 29335246
2018 Exosomes derived miR-126 attenuates oxidative stress and apoptosis from ischemia and reperfusion injury by targeting ERRFI1. Gene 51 30597234
2020 Glioma exosomal microRNA-148a-3p promotes tumor angiogenesis through activating the EGFR/MAPK signaling pathway via inhibiting ERRFI1. Cancer cell international 47 33117083
2014 Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation. Proceedings of the National Academy of Sciences of the United States of America 46 24550287
2012 Cancer-type regulation of MIG-6 expression by inhibitors of methylation and histone deacetylation. PloS one 45 22701735
2014 Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation. Cancer research 40 25377472
2005 Targeted expression of RALT in mouse skin inhibits epidermal growth factor receptor signalling and generates a Waved-like phenotype. EMBO reports 39 16007071
2009 Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis. Development (Cambridge, England) 37 19710174
2011 Downregulation of Mig-6 in nonsmall-cell lung cancer is associated with EGFR signaling. Molecular carcinogenesis 36 21739478
2022 Loss of MIG-6 results in endometrial progesterone resistance via ERBB2. Nature communications 35 35232969
1989 Overproduced bacteriophage T4 gene 33 protein binds RNA polymerase. Journal of bacteriology 34 2722758
1989 Rat gene 33: analysis of its structure, messenger RNA and basal promoter activity. Nucleic acids research 32 2780291
2006 Gene 33/RALT is induced by hypoxia in cardiomyocytes, where it promotes cell death by suppressing phosphatidylinositol 3-kinase and extracellular signal-regulated kinase survival signaling. Molecular and cellular biology 30 16782890
2019 ERRFI1 Inhibits Proliferation and Inflammation of Nucleus Pulposus and Is Negatively Regulated by miR-2355-5p in Intervertebral Disc Degeneration. Spine 29 30817728
2013 Critical tumor suppressor function mediated by epithelial Mig-6 in endometrial cancer. Cancer research 29 23811943
2007 Generation of a Mig-6 conditional null allele. Genesis (New York, N.Y. : 2000) 29 17987665
2002 A novel mechanism of nuclear factor kappaB activation through the binding between inhibitor of nuclear factor-kappaBalpha and the processed NH(2)-terminal region of Mig-6. Cancer research 29 12384522
2019 Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation. Journal of cellular physiology 26 31313286
2018 miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling. EMBO molecular medicine 26 30021798
1999 Molecular cloning of a major Alternaria alternata allergen, rAlt a 2. The Journal of allergy and clinical immunology 26 10482844
2012 Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis. PloS one 25 22912762
2020 A novel role of the miR-152-3p/ERRFI1/STAT3 pathway modulates the apoptosis and inflammatory response after acute kidney injury. Journal of biochemical and molecular toxicology 24 32583487
2012 Chk1 phosphorylates the tumour suppressor Mig-6, regulating the activation of EGF signalling. The EMBO journal 23 22505024
2020 Long noncoding RNA ANRIL promotes the malignant progression of cholangiocarcinoma by epigenetically repressing ERRFI1 expression. Cancer science 21 32378752
2021 Gene 33/Mig6/ERRFI1, an Adapter Protein with Complex Functions in Cell Biology and Human Diseases. Cells 19 34206547
2005 Gene 33 inhibits apoptosis of breast cancer cells and increases poly(ADP-ribose) polymerase expression. Breast cancer research and treatment 19 15952054
2021 ERRFI1 induces apoptosis of hepatocellular carcinoma cells in response to tryptophan deficiency. Cell death discovery 17 34608122
2017 Mig-6 is down-regulated in HCC and inhibits the proliferation of HCC cells via the P-ERK/Cyclin D1 pathway. Experimental and molecular pathology 17 28506767
2022 Hypermethylation of Mig-6 gene promoter region inactivates its function, leading to EGFR/ERK signaling hyperphosphorylation, and is involved in arsenite-induced hepatic stellate cells activation and extracellular matrix deposition. Journal of hazardous materials 16 35850069
2016 Gene 33/Mig6 inhibits hexavalent chromium-induced DNA damage and cell transformation in human lung epithelial cells. Oncotarget 16 26760771
2014 Amelioration of hypercholesterolemia by an EGFR tyrosine kinase inhibitor in mice with liver-specific knockout of Mig-6. PloS one 16 25486251
2017 MIG-6 negatively regulates STAT3 phosphorylation in uterine epithelial cells. Oncogene 15 28925396
1995 Inhibitors of signalling identify differential control processes responsible for selective effects of insulin on the expression of phosphoenolpyruvate carboxykinase and gene 33 in rat H4 hepatoma cells. The Biochemical journal 15 7654170
2020 Differential Glucocorticoid-Dependent Regulation and Function of the ERRFI1 Gene in Triple-Negative Breast Cancer. Endocrinology 14 32432675
2015 Understanding the molecular basis of EGFR kinase domain/MIG-6 peptide recognition complex using computational analyses. BMC bioinformatics 14 25885222
2015 Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling. Biochemical and biophysical research communications 14 25976672
1994 Molecular genetic analysis of a prokaryotic transcriptional coactivator: functional domains of the bacteriophage T4 gene 33 protein. Journal of bacteriology 14 8106327
2021 MIG-6 is essential for promoting glucose metabolic reprogramming and tumor growth in triple-negative breast cancer. EMBO reports 13 33655623
2020 Suppression of Mig-6 overcomes the acquired EGFR-TKI resistance of lung adenocarcinoma. BMC cancer 13 32552717
2017 Mig-6 deficiency cooperates with oncogenic Kras to promote mouse lung tumorigenesis. Lung cancer (Amsterdam, Netherlands) 13 29191600
2005 Increased MIG-6 mRNA transcripts in osteoarthritic cartilage. Biochemical and biophysical research communications 13 15910752
1999 Activation of stress-activated protein kinases by hepatocyte isolation induces gene 33 expression. Biochemical and biophysical research communications 13 9920809
1994 Synergistic induction of gene 33 expression by retinoic acid and insulin. Endocrinology 13 8156927
2024 ERRFI1 exacerbates hepatic ischemia reperfusion injury by promoting hepatocyte apoptosis and ferroptosis in a GRB2-dependent manner. Molecular medicine (Cambridge, Mass.) 12 38862918
2016 Inhibition of Cdc42 is essential for Mig-6 suppression of cell migration induced by EGF. Oncotarget 12 27341132
2017 Mig-6 Mouse Model of Endometrial Cancer. Advances in experimental medicine and biology 11 27910070
2017 MicroRNA-374a Promotes Hepatocellular Carcinoma Cell Proliferation by Targeting Mitogen-Inducible Gene 6 (MIG-6). Oncology research 11 28734040
2014 Mig-6 overcomes gefitinib resistance by inhibiting EGFR/ERK pathway in non-small cell lung cancer cell lines. International journal of clinical and experimental pathology 11 25400829
1992 Insulin increases transcription of rat gene 33 through cis-acting elements in 5'-flanking DNA. Gene 11 1511896
2020 Overexpression of MIG-6 in the cartilage induces an osteoarthritis-like phenotype in mice. Arthritis research & therapy 10 32430054
2018 MIG-6 suppresses endometrial epithelial cell proliferation by inhibiting phospho-AKT. BMC cancer 10 29843645
2017 Nuclear Gene 33/Mig6 regulates the DNA damage response through an ATM serine/threonine kinase-dependent mechanism. The Journal of biological chemistry 10 28842482
2015 Role of Mig-6 in hepatic glucose metabolism. Journal of diabetes 10 25594850
2000 Insulin-induced gene 33 mRNA expression in Chinese hamster ovary cells is insulin receptor dependent. Journal of cellular biochemistry 10 10760951
2022 Mig-6 Inhibits Autophagy in HCC Cell Lines by Modulating miR-193a-3p. International journal of medical sciences 9 35165519
2014 Mig-6 gene knockout induces neointimal hyperplasia in the vascular smooth muscle cell. Disease markers 9 25574067
2020 An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer. BMC medical genomics 8 31969149
2014 Mig-6 participates in the regulation of cell senescence and retinoblastoma protein phosphorylation. Cellular signalling 8 24815188
2021 Mig-6 could inhibit cell proliferation and induce apoptosis in esophageal squamous cell carcinoma. Thoracic cancer 7 34845855
2019 The Role of ERRFI1+808T/G Polymorphism in Diabetic Nephropathy. International journal of molecular and cellular medicine 7 32351909
2016 Expression and regulation of the differentiation regulators ERBB Receptor Feedback Inhibitor 1 (ERRFI1) and Interferon-related Developmental Regulator 1 (IFRD1) during the periovulatory period in the rat ovary. Molecular reproduction and development 7 27358163
2007 Expression of MIG-6, WNT-9A, and WNT-7B during osteoarthritis. Annals of the New York Academy of Sciences 7 18056042
1997 Characterization of the proteinase specified by varicella-zoster virus gene 33. The Journal of general virology 7 9292001
1992 Vanadate and insulin stimulate gene 33 expression. Biochemical and biophysical research communications 7 1472065
2021 Capilliposide C from Lysimachia capillipes Restores Radiosensitivity in Ionizing Radiation-Resistant Lung Cancer Cells Through Regulation of ERRFI1/EGFR/STAT3 Signaling Pathway. Frontiers in oncology 6 33869036
2014 Decreased Mitogen Inducible Gene 6 (MIG-6) Associated with Symptom Severity in Children with Autism. Biomarker insights 6 25342879
1997 Secondary structure of T4 gene 33 protein. Fourier transform infrared and circular dichroic spectroscopic studies. International journal of biological macromolecules 5 9184943
1983 [Transmission of amber mutants in bacteriophage T4. II. Thermal sensitivity of the multiplication of gene 26 amber mutants in Escherichia coli B cells and the absence of such sensitivity in the case of gene 33]. Genetika 5 6684608
2022 MIG-6 Is Critical for Progesterone Responsiveness in Human Complex Atypical Hyperplasia and Early-Stage Endometrial Cancer. International journal of molecular sciences 4 36498921
2019 A calcium-dependent phospholipase A2 (cPLA2) expression is regulated by MIG-6 during endometrial tumorigenesis. Biochemical and biophysical research communications 4 30773264
2019 AAV-Mig-6 Increase the Efficacy of TAE in VX2 Rabbit Model, Is Associated With JNK Mediated Autophagy. Journal of Cancer 4 30854112
2013 Novel ERBB receptor feedback inhibitor 1 (ERRFI1) + 808 T/G polymorphism confers protective effect on diabetic nephropathy in a Korean population. Disease markers 4 23324575
2022 KLF4 Affects Acute Renal Allograft Injury via Binding to MicroRNA-155-5p Promoter to Regulate ERRFI1. Disease markers 3 35340414
2024 Potentially functional variants of ERRFI1 in hypoxia-related genes predict survival of non-small cell lung cancer patients. Cancer medicine 2 39096122
2024 Construction of ceRNA Network and Disease Diagnosis Model for Keloid Based on Tumor Suppressor ERRFI1. Experimental dermatology 2 39563082
1999 Insulin and phorbol ester regulation of gene 33 expression in CHO cells. Puerto Rico health sciences journal 2 10547870
2025 MIG-6 Plays a Critical Role as a PGR Mediator in Maintaining Epithelial and Stromal Cells for Uterine Receptivity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 40905903
2023 The increased expression of cytokeratin 13 leads to an increase in radiosensitivity of nasopharyngeal carcinoma HNE-3 cells by upregulating ERRFI1. IUBMB life 1 37070291
2023 Precision oncology strategy in cetuximab-resistant ERRFI1-mutant colon cancer: case report of disease progression on afatinib. American journal of translational research 1 37854204