Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10.
Idiopathic pulmonary fibrosis is a disease that is characterized by fibroblast accumulation and activation in the distal airspaces of the lung. We hypothesized that fibrotic lung fibroblasts migrate/invade across basement membranes by integrin-mediated mechanisms as a means of entering alveoli. We demonstrate that in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis, fibronectin signaling is both necessary and sufficient for basement membrane migration/invasion across basement membranes. This effect is mediated through the alpha5beta1 integrin because blockade of fibronectin-alpha5 integrin ligation attenuated this response. In contrast, ligation of alpha4beta1 integrin inhibits basement membrane invasion by normal lung fibroblasts but not by fibrotic lung fibroblasts. This phenotypic difference is not related to surface expression of the alpha4beta1 integrin, as demonstrated by flow cytometry. In normal lung fibroblasts but not in fibrotic lung fibroblasts, we show that ligation of alpha4beta1 integrin induces a significant increase in phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activity. Fibrotic lung fibroblasts express constitutively less PTEN mRNA and protein as well as phosphatase activity in comparison to normal lung fibroblasts. Together, these data suggest that a loss of alpha4beta1 signaling via PTEN confers a migratory/invasive phenotype to fibrotic lung fibroblasts. Furthermore, this study implicates a loss of PTEN function in the pathophysiology of idiopathic pulmonary fibrosis.
White
Eric S
ES
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, 6301 MSRB III/0642, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0642, USA. docew@umich.edu
Thannickal
Victor J
VJ
Carskadon
Shannon L
SL
Dickie
Emily G
EG
Livant
Donna L
DL
Markwart
Sonja
S
Toews
Galen B
GB
Arenberg
Douglas A
DA
D000704:Analysis of Variance; D001485:Basement Membrane / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology*; D005353:Fibronectins / Q000502:physiology; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology*; D008168:Lung / Q000473:pathology*; D051059:PTEN Phosphohydrolase; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D005353:Fibronectins; D039041:Integrin alpha4beta1; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human