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: Nili Jin, Sung-Nam Cho, M Gabriela Raso, Ignacio Wistuba, Yvonne Smith, Yanan Yang, Jonathan M Kurie, Rudolph Yen, Christopher M Evans, Thomas Ludwig, Jae-Wook Jeong, Francesco J DeMayo
• Journal: Development (Cambridge, England) (Development) Vol. 136 Issue 19 Pg. 3347-56 (Oct 2009) ISSN: 1477-9129 [Electronic] England
• PMID: 19710174 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• DNA Primers
• ERRFI1 protein, human
• Errfi1 protein, mouse
• Intracellular Signaling Peptides and Proteins
• Tumor Suppressor Proteins
• ErbB Receptors

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, deficiency, genetics, physiology)
• Animals
• Animals, Newborn
• Apoptosis
• Base Sequence
• Bronchioles (cytology, metabolism)
• Cell Proliferation
• Cells, Cultured
• DNA Primers (genetics)
• Endothelial Cells (cytology, metabolism)
• ErbB Receptors (metabolism)
• Female
• Gene Expression Regulation, Developmental
• Homeostasis
• Humans
• Intracellular Signaling Peptides and Proteins
• Lung (blood supply, embryology, growth & development, physiology)
• Mice
• Mice, Knockout
• Neovascularization, Physiologic
• Pregnancy
• RNA Interference
• Signal Transduction
• Tumor Suppressor Proteins