title: Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis.
abstract: Mitogen-inducible gene 6 [Mig-6; Errfi1 (ErbB receptor feedback inhibitor 1); RALT (receptor-associated late transducer); gene 33] is a ubiquitously expressed adaptor protein containing CRIB, SH3 and 14-3-3 interacting domains and has been shown to negatively regulate EGF signaling. Ablation of Mig-6 results in a partial lethal phenotype in which surviving mice acquire degenerative joint diseases and tumors in multiple organs. We have determined that the early lethality in Mig-6(-/-) mice occurs in the perinatal period, with mice displaying abnormal lung development. Histological examination of Mig-6(-/-) lungs (E15.5-P3) revealed reduced septation, airway over-branching, alveolar type II cell hyperplasia, and disturbed vascular formation. In neonatal Mig-6(-/-) lungs, cell proliferation increased in the airway epithelium but apoptosis increased in the blood vessels. Adult Mig-6(-/-) mice developed features of chronic obstructive pulmonary disease (COPD); however, when Mig-6 was inducibly ablated in adult mice (Mig-6(d/d)), the lungs were normal. Knockdown of MIG-6 in H441 human bronchiolar epithelial cells increased phospho-EGFR and phospho-AKT levels as well as cell proliferation, whereas knockdown of MIG-6 in human lung microvascular endothelial (HMVEC-L) cells promoted their apoptosis. These results demonstrate that Mig-6 is required for prenatal and perinatal lung development, in part through the regulation of EGF signaling, as well as for maintaining proper pulmonary vascularization.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nili
authors.initials: N
authors.lastname: Jin
authors.forename: Sung-Nam
authors.initials: SN
authors.lastname: Cho
authors.forename: M Gabriela
authors.initials: MG
authors.lastname: Raso
authors.forename: Ignacio
authors.initials: I
authors.lastname: Wistuba
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Smith
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yang
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
authors.forename: Rudolph
authors.initials: R
authors.lastname: Yen
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Jeong
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001483:Base Sequence; D055745:Bronchioles / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000098:blood supply / Q000196:embryology / Q000254:growth & development* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D034622:RNA Interference; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C484017:ERRFI1 protein, human; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors