<i>Mig-6</i>is required for appropriate lung development and to ensure normal adult lung homeostasis

Jin, Nili; Cho, Sung Nam; Raso, Maria Gabriela; Wistuba, Ignacio I.; Smith, Yvonne E.; Yang, Yanan; Kurie, Jonathan M.; Yen, Rudolph; Evans, Christopher M.; Ludwig, Thomas; Jeong, Jae Wook; DeMayo, Francesco J.

doi:10.1242/dev.032979

Cited by 41 publications

(53 citation statements)

References 64 publications

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“…Tissue-specific knockout of Mig6 increases EGFR signaling and the proliferation of epithelial cells in mouse lungs, suggesting that Mig6 is essential for lung homeostasis (34). Deletion of Mig6 in mice also promotes adenomas and adenocarcinomas in the lung, gallbladder, and bile duct, albeit at low penetrance (30).…”

Section: Resultsmentioning

confidence: 99%

Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma

et al. 2015

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Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here we demonstrate that Mig6 is a tumor suppressor for the initiation and progression of mutant EGFR-driven lung adenocarcinoma in mouse models. Mutant EGFR-induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 haploinsufficiency. We demonstrate that constitutive phosphorylation of MIG6 at Y394/395 in EGFR-mutant human lung adenocarcinoma cell lines is associated with an increased interaction of MIG6 with mutant EGFR, which may stabilize EGFR protein. MIG6 also fails to promote mutant EGFR degradation. We propose a model whereby increased tyrosine phosphorylation of MIG6 decreases its capacity to inhibit mutant EGFR. Nonetheless, the residual inhibition is sufficient for Mig6 to delay mutant EGFR-driven tumor initiation and progression in mouse models.

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Section: Resultsmentioning

confidence: 99%

Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma

et al. 2015

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“…EGFR IFIs are expected to provide a key balance to these positive feedback loops, because (i) LRIG1, SOCS4 and/or SOCS5 might promote ligand-independent EGFR degradation; (ii) RALT inhibits EGFR catalytic function regardless of the activating ligand (Anastasi et al, 2007); and (iii) LRIG1, SOCS4, SOCS5 and RALT antagonise the activity of all ErbB family members, including ERBB2, which acts as a signal amplifier. Consistent with this view, levels of EGFR ligands, such as heparin-binding EGF-like growth factor (HB-EGF), which activates both EGFR and ErbB4, and amphiregulin, which stimulates EGFR without inducing receptor degradation, are increased in the lung and liver of Errfi1 -/-mice (Reschke et al, 2010;Jin et al, 2009), which might be regarded as both a consequence and cause of the unabated EGFR activity generated by unbalanced feedback control. that in control littermates.…”

Section: Box 2 Inducible Feedback Inhibitors As Gatekeepers Of Egfr mentioning

confidence: 85%

“…Errfi1 -/-mice also show a perinatal lung phenotype associated with hyperproliferation of epithelial cells in bronchi and alveoli (Jin et al, 2009). This phenotype is probably caused by excessive EGFR signalling because the alveolar and vascular lesions of Errfi1 -/-mice, first, are reminiscent of those observed in mice with conditional perinatal overexpression of TGF (Le Cras et al, 2004), second, develop in a timeframe characterised by a burst of expression of Errfi1 mRNA in the lung of normal mice (Jin et al, 2009) and, third, are associated with increased EGFR signalling and overexpression of EGFR ligands in lung epithelial cells (Jin et al, 2009).…”

Section: Errfi1mentioning

confidence: 99%

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

Segatto¹,

Anastasi²,

Alemà

2011

Journal of Cell Science

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Signalling by the epidermal growth factor receptor (EGFR) controls morphogenesis and/or homeostasis of several tissues from worms to mammals. The correct execution of these programmes requires the generation of EGFR signals of appropriate strength and duration. This is obtained through a complex circuitry of positive and negative feedback regulation. Feedback inhibitory mechanisms restrain EGFR activity in time and space, which is key to ensuring that receptor outputs are commensurate to the cell and tissue needs. Here, we focus on the emerging field of inducible negative feedback regulation of the EGFR in mammals. In mammalian cells, four EGFR inducible feedback inhibitors (IFIs), namely LRIG1, RALT (also known as MIG6 and ERRFI1), SOCS4 and SOCS5, have been discovered recently. EGFR IFIs are expressed de novo in the context of early or delayed transcriptional responses triggered by EGFR activation. They all bind to the EGFR and suppress receptor signalling through several mechanisms, including catalytic inhibition and receptor downregulation. Here, we review the mechanistic basis of IFI signalling and rationalise the function of IFIs in light of gene-knockout studies that assign LRIG1 and RALT an essential role in restricting cell proliferation. Finally, we discuss how IFIs might participate in system control of EGFR signalling and highlight the emerging roles for IFIs in the suppression of EGFR-driven tumorigenesis.

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“…Mig-6 is best known for its ability to attenuate EGFR signaling via a negative feedback loop by interacting with EGFR and its downstream signaling molecules (3)(4)(5)(6)(7). It may function as a tumor suppressor and play roles in developmental and physiological processes such as skin morphogenesis and lung development (8)(9)(10). Mig-6 plays an essential role in the postnatal synovial joints: Mice with a Mig-6 deficiency develop early-onset osteoarthritis (OA)-like disorder in the knee, ankle, and temporal-mandibular joint (TMJ) (11).…”

mentioning

confidence: 99%

Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation

Staal

Williams

Beier

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Mitogen-inducible gene 6 (Mig-6) was found to be an important factor in maintaining joint homeostasis, and its loss in mice results in the development of an osteoarthritis (OA)-like disorder in multiple synovial joints. However, it was unclear in what cells Mig-6 was expressed and what cells were causal for developing the OA-like phenotype. Here we report that Mig-6 is uniquely expressed in the cells surrounding entire surface of the synovial joint, including chondrocytes in the superficial zone of the articular cartilage and in the meniscus, and synovial lining cells. We found that although chondrocytes play a critical role in developing the OA-like disorder in the knees, other cell types are likely required for full development of the Mig-6–deficient joint phenotype.

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Mig-6is required for appropriate lung development and to ensure normal adult lung homeostasis

Cited by 41 publications

References 64 publications

Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma

Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

Cartilage-specific deletion of Mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation

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