Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis.
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.
Jin
Nili
N
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Cho
Sung-Nam
SN
Raso
M Gabriela
MG
Wistuba
Ignacio
I
Smith
Yvonne
Y
Yang
Yanan
Y
Kurie
Jonathan M
JM
Yen
Rudolph
R
Evans
Christopher M
CM
Ludwig
Thomas
T
Jeong
Jae-Wook
JW
DeMayo
Francesco J
FJ
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
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