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Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable fibroproliferative disorder characterized by unrelenting proliferation of fibroblasts and their deposition of collagen within alveoli, resulting in permanently scarred, nonfunctional airspaces. Normally, polymerized collagen suppresses fibroblast proliferation and serves as a physiological restraint to limit fibroproliferation after tissue injury. The IPF fibroblast, however, is a pathologically altered cell that has acquired the capacity to elude the proliferation-suppressive effects of polymerized collagen. The mechanism for this phenomenon remains incompletely understood. Here, we demonstrate that expression of α2β1 integrin, a major collagen receptor, is pathologically low in IPF fibroblasts interacting with polymerized collagen. Low integrin expression in IPF fibroblasts is associated with a failure to induce PP2A phosphatase activity, resulting in abnormally high levels of phosphorylated (inactive) GSK-3β and high levels of active β-catenin in the nucleus. Knockdown of β-catenin in IPF fibroblasts inhibits their ability to proliferate on collagen. Interdiction of α2β1 integrin in control fibroblasts reproduces the IPF phenotype and leads to the inability of these cells to activate PP2A, resulting in high levels of phosphorylated GSK-3β and active β-catenin and in enhanced proliferation on collagen. Our findings indicate that the IPF fibroblast phenotype is characterized by low α2β1 integrin expression, resulting in a failure of integrin to activate PP2A phosphatase, which permits inappropriate activation of the β-catenin pathway. Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable fibroproliferative disorder characterized by unrelenting proliferation of fibroblasts and their deposition of collagen within alveoli, resulting in permanently scarred, nonfunctional airspaces. Normally, polymerized collagen suppresses fibroblast proliferation and serves as a physiological restraint to limit fibroproliferation after tissue injury. The IPF fibroblast, however, is a pathologically altered cell that has acquired the capacity to elude the proliferation-suppressive effects of polymerized collagen. The mechanism for this phenomenon remains incompletely understood. Here, we demonstrate that expression of α2β1 integrin, a major collagen receptor, is pathologically low in IPF fibroblasts interacting with polymerized collagen. Low integrin expression in IPF fibroblasts is associated with a failure to induce PP2A phosphatase activity, resulting in abnormally high levels of phosphorylated (inactive) GSK-3β and high levels of active β-catenin in the nucleus. Knockdown of β-catenin in IPF fibroblasts inhibits their ability to proliferate on collagen. Interdiction of α2β1 integrin in control fibroblasts reproduces the IPF phenotype and leads to the inability of these cells to activate PP2A, resulting in high levels of phosphorylated GSK-3β and active β-catenin and in enhanced proliferation on collagen. Our findings indicate that the IPF fibroblast phenotype is characterized by low α2β1 integrin expression, resulting in a failure of integrin to activate PP2A phosphatase, which permits inappropriate activation of the β-catenin pathway. Idiopathic pulmonary fibrosis (IPF) is a prevalent and progressive fibroproliferative lung disease that is incurable. Histologically, the fibroblastic focus is the major morphological lesion of IPF. It consists of fibroblasts in a type I collagen-rich matrix.1Kuhn 3rd, C. McDonald J.A. The roles of the myofibroblast in idiopathic pulmonary fibrosis Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis.Am J Pathol. 1991; 138: 1257-1265PubMed Google Scholar The disease is characterized by unrelenting progression of fibrotic tissue formation, with expansion of fibroblasts within alveolar walls and deposition of type I collagen resulting in the obliteration of airspaces and subsequent impairment of gas exchange that in turn leads to progressive hypoxia.2American Thoracic Society (ATS)European Respiratory Society (ERS)Idiopathic pulmonary fibrosis: diagnosis and treatment International consensus statement.Am J Respir Crit Care Med. 2000; 161: 646-664Crossref PubMed Scopus (1007) Google Scholar, 3Basset F. Ferrans V.J. Soler P. Takemura T. Fukuda Y. Crystal R.G. Intraluminal fibrosis in interstitial lung disorders.Am J Pathol. 1986; 122: 443-461PubMed Google Scholar, 4Fukuda Y. Ishizaki M. Masuda Y. Kimura G. Kawanami O. Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage.Am J Pathol. 1987; 126: 171-182PubMed Google Scholar, 5Kuhn 3rd, C. Boldt J. King Jr, T.E. Crouch E. Vartio T. McDonald J.A. An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis.Am Rev Respir Dis. 1989; 140: 1693-1703Crossref PubMed Scopus (397) Google Scholar Fibrillar type I collagen, a potent suppressor of normal fibroblast proliferation, functions as a physiological restraint to limit fibroproliferation after injury.6Koyama H. Raines E.W. Bornfeldt K.E. Roberts J.M. Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors.Cell. 1996; 87: 1069-1078Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, 7Schor S.L. Cell proliferation and migration on collagen substrata in vitro.J Cell Sci. 1980; 41: 159-175Crossref PubMed Google Scholar, 8Rhudy R.W. McPherson J.M. Influence of the extracellular matrix on the proliferative response of human skin fibroblasts to serum and purified platelet-derived growth factor.J Cell Physiol. 1988; 137: 185-191Crossref PubMed Scopus (36) Google Scholar The β1 integrin is a cell surface matrix receptor that is critically positioned at the apex of signaling pathways that regulate proliferation.9Ruoslahti E. Integrin signaling and matrix assembly.Tumour Biol. 1996; 17: 117-124Crossref PubMed Scopus (124) Google Scholar, 10Khwaja A. Rodriguez-Viciana P. Wennström S. Warne P.H. Downward J. 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PubMed Scopus Google Scholar, Integrin and induce of and to PubMed Scopus Google Scholar, Integrin regulation of and a survival mechanism for Cell Biol. PubMed Scopus Google Scholar, Y. Roberts cell transformation through the activation of Full Text Full Text PDF PubMed Scopus Google Scholar that integrin signaling the proliferative capacity of human IPF lung H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar, H. J. J. J. regulation of in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus (124) Google Scholar that β1 integrin with polymerized collagen suppresses normal fibroblast proliferation by of the of high phosphatase IPF fibroblasts this a of β1 integrin signaling in response to polymerized collagen that in activation of the low It has however, integrin regulation of IPF fibroblast proliferation through the pathways α2β1 integrin is the major type I collagen receptor, in IPF fibroblasts the role that α2β1 integrin in proliferation signaling has that β-catenin is in M. A. M. P. S. M. A. A. R. G. C. activation in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. O. signaling is in idiopathic pulmonary PubMed Scopus Google Scholar the mechanism by which β-catenin is in IPF remains incompletely understood. that α2β1 integrin expression is IPF fibroblasts on polymerized type I collagen, with control a and J. J. Integrin activation of protein phosphatase and of and kinase Cell Biol. PubMed Scopus Google Scholar that α2β1 integrin is for activation of the phosphatase PP2A cell with type I collagen. Here, we demonstrate that low α2β1 integrin expression in the failure of IPF fibroblasts to induce PP2A phosphatase interacting with collagen. is associated with high levels of phosphorylated (inactive) a PP2A and high levels of active demonstrate that of β-catenin the ability of IPF fibroblasts to proliferate on polymerized collagen. findings in to for control which levels of α2β1 integrin and induce PP2A activity, GSK-3β and demonstrate that of α2β1 by of β1 integrin expression in control fibroblasts in the inability of these cells to induce PP2A phosphatase these cells with polymerized collagen. Interdiction of α2β1 integrin in control fibroblasts the of phosphorylated (inactive) the of active and control fibroblast proliferation on polymerized collagen, IPF fibroblast Our findings indicate that the IPF fibroblast phenotype is characterized by abnormally low α2β1 integrin expression and which is to the failure to induce PP2A phosphatase activity, and the activation of the β-catenin proliferation pathway. fibroblast IPF at the of The diagnosis of IPF by pulmonary and findings of IPF. the diagnosis of IPF by of lung which the morphological findings of interstitial patients the for the diagnosis of IPF as by the Thoracic Society and the Respiratory Thoracic Respiratory Thoracic Respiratory Society International of the Idiopathic of the Thoracic Society and the Respiratory Society by the of and by the in J Respir Crit Care J Respir Crit Care Med. PubMed Scopus Google Scholar control human lung fibroblast fibroblasts normal lung tissue at the of lung and normal lung tissue fibrotic lung tissue lung fibroblast by and in to characterized as fibroblasts as J. R. J. M. P. cells after lung enhanced proliferative PubMed Scopus Google Scholar of human by the at the of integrin and Cell and active integrin, polymerized collagen by the collagen with of and to a with to which serum at a of after of this at for to as J. J. integrin fibroblast collagen matrix through a kinase signaling Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. J. adhesion kinase is of in fibroblast survival in response to of type I collagen a integrin signaling Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. J. of kinase in of and fibroblast survival in type I collagen through a integrin signaling Full Text Full Text PDF PubMed Scopus Google Scholar, H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar β1 and control the of The the The cells with at a of of IPF and control fibroblasts with a β1 integrin, β1 integrin control fibroblasts on extracellular and at the cell and with on the resulting for and on polymerized collagen matrix in with the cells polymerized collagen the with with The cells with for the cells at The cells with to synthesis and as a of synthesis by the of cells by cell to the PP2A by of the cell with of with with PP2A with and and of the to the The by of PP2A a at on IPF and control lung tissue a to integrin a to β1 integrin and and to muscle at on IPF and control fibroblasts on The cells and with the The cells with by with on lung tissue a to human integrin and a to human β1 integrin The through a of and in for The with in to and with normal human serum and sites with and and with by of by as a of with the the a of as Our that IPF fibroblasts the proliferation-suppressive effects of polymerized type I H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar, H. J. J. J. regulation of in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus (124) Google Scholar The mechanism β1 integrin resulting in activation of the proliferation pathway. α2β1 integrin is the major integrin that with type I collagen, we to the role that α2β1 in proliferation signaling and in IPF β1 integrin expression by in lung fibroblasts IPF patients and control patients and on polymerized type I collagen the of activation of proliferation signaling of H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar, H. J. J. J. regulation of in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus (124) Google Scholar we that β1 integrin expression high in IPF we that β1 integrin protein expression in IPF fibroblasts on polymerized collagen, with control fibroblasts to for β1 integrin, we that integrin expression in IPF with control the β1 integrin activation of IPF and control fibroblasts on polymerized collagen as a of a in the of β1 integrin in IPF with control at integrin expression with proliferation, we the proliferative capacity of IPF and control fibroblasts on polymerized collagen. with we that the ability of IPF fibroblasts to proliferate on polymerized collagen with control fibroblasts H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar IPF fibroblast with type I collagen, the expression of α2β1 integrin is low and the proliferative capacity is with control low α2β1 integrin levels in IPF fibroblasts in with α2β1 integrin expression in we α2β1 integrin expression in fibroblasts within type I collagen-rich fibroblastic in human IPF lung tissue by and β1 integrin we that cells within IPF fibroblastic for β1 integrin, with cells the fibroblastic which for and β1 integrin within the fibrotic for smooth muscle a of integrin in IPF and control we the of and β1 in cells and at The integrin expression in both IPF and control is with to and β1 integrin in the of normal lung of integrin cell adhesion in normal and lung J Respir Cell Biol. PubMed Scopus Google Scholar, A. T. P. expression of and their integrin in and human J Respir Cell Biol. 1996; PubMed Scopus Google Scholar with of integrin cell adhesion in normal and lung J Respir Cell Biol. PubMed Scopus Google Scholar diffuse and β1 in cells normal alveolar we with of IPF lung tissue that fibroblastic a of cells for and β1 integrin, for both and β1 in cells the fibrotic at of and β1 integrin in cells normal alveolar in control lung tissue that α2β1 integrin expression is low in IPF fibroblasts with that proliferation pathways integrin pathologically in we that in integrin to of that proliferation of this and J. J. Integrin activation of protein phosphatase and of and kinase Cell Biol. PubMed Scopus Google Scholar that α2β1 cell adhesion to collagen to the of of the phosphatase to that pathologically low α2β1 integrin in IPF fibroblasts to induce PP2A these cells with collagen. with this we that IPF fibroblast with polymerized collagen a these cells to induce PP2A phosphatase control fibroblasts PP2A PP2A in control with IPF the low PP2A in IPF fibroblasts interacting with collagen to a of PP2A expression a failure to activate the phosphatase, we the expression of the of PP2A in IPF and control fibroblasts on polymerized collagen for IPF and control fibroblasts expression in IPF with control fibroblasts expression, in both IPF and control with to that pathologically low α2β1 integrin to induce PP2A phosphatase IPF fibroblast with polymerized collagen, normal α2β1 integrin in control fibroblasts activation of the role of α2β1 integrin in PP2A in IPF and control we integrin that has to of integrin the of PP2A in control fibroblasts in PP2A in cells with with PP2A low in IPF fibroblasts and in response to the α2β1 that the of α2β1 integrin PP2A activity, we β1 integrin expression in control to β1 The cells on polymerized collagen, and PP2A phosphatase as a of PP2A in control cells with control with control cells in which β1 integrin that integrin expression PP2A we β1 integrin in IPF as as the β1 integrin β1 H. M. A. M. Matrix progression by integrin Full Text Full Text PDF PubMed Scopus Google Scholar as a of of the β1 integrin by IPF however, and we a of with that the of α2β1 integrin PP2A activity, we which α2β1 integrin, and fibroblasts with α2β1 integrin on polymerized collagen and PP2A PP2A cells with polymerized collagen, with which of α2β1 integrin and to polymerized collagen, to activate PP2A α2β1 with integrin control the that α2β1 integrin expression in IPF fibroblasts in a failure of these cells to activate PP2A in response to with polymerized type I collagen. PP2A phosphatase has to for phosphatase a of Cell Biol. 2000; PubMed Scopus Google Scholar phosphatase a of Cell Biol. 2000; PubMed Scopus Google Scholar that PP2A and that in IPF fibroblasts in response to their with collagen, the of low in control H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar PP2A with in control fibroblasts their with polymerized collagen. we to a of PP2A with in control fibroblasts the of the PP2A on the of in control fibroblasts on polymerized collagen. a in the of in control fibroblasts with the PP2A these indicate that is a major for PP2A in control fibroblasts their with polymerized collagen. The β-catenin has to in M. A. M. P. S. M. A. A. R. G. C. activation in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. O. signaling is in idiopathic pulmonary PubMed Scopus Google Scholar GSK-3β has to a for GSK-3β is active and inhibits phosphatase a of Cell Biol. 2000; PubMed Scopus Google Scholar we the of phosphorylated (inactive) GSK-3β in IPF and control fibroblasts on polymerized collagen as a of with a failure of IPF fibroblasts to activate PP2A in response to with collagen, we that the of phosphorylated (inactive) in IPF with control control however, the of GSK-3β with PP2A PP2A control fibroblast with collagen, the of GSK-3β that low PP2A phosphatase in IPF fibroblasts in levels of phosphorylated (inactive) GSK-3β for J. M. J. C. R. M. of with and PubMed Scopus Google Scholar we that the of GSK-3β is high in IPF fibroblasts on polymerized collagen, we that active β-catenin levels with this we that the of active β-catenin in IPF fibroblasts on polymerized collagen, with control fibroblasts at of control fibroblast with polymerized collagen, a PP2A is high the levels of both GSK-3β and active β-catenin the that α2β1 integrin levels in low PP2A in IPF which leads to of GSK-3β and levels of active the of active β-catenin in IPF and control fibroblasts on polymerized collagen by with as a active β-catenin in the of IPF fibroblasts on collagen. β-catenin in control fibroblasts with high levels of active β-catenin in M. A. M. P. S. M. A. A. R. G. C. activation in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. O. signaling is in idiopathic pulmonary PubMed Scopus Google Scholar of α2β1 integrin and levels of PP2A low in IPF and the of phosphorylated GSK-3β is the in control in which α2β1 integrin expression and PP2A levels high the of phosphorylated GSK-3β is a integrin and the role of α2β1 integrin in GSK-3β and β-catenin in IPF and control we the integrin of α2β1 by the the expression of phosphorylated (inactive) GSK-3β expression and the of active β-catenin in control fibroblasts with polymerized collagen of α2β1 by the the of GSK-3β expression active β-catenin in IPF α2β1 integrin expression is low in IPF resulting in a failure of these cells to activate that integrin expression the of phosphorylated GSK-3β in we the of of β1 integrin on the of phosphorylated GSK-3β and active β-catenin in control Knockdown the of β1 integrin response to of β1 integrin, the of with control fibroblasts with control with the that of β1 integrin of in of the of active β-catenin indicate that β1 integrin in the and of β-catenin that the of α2β1 the levels of and active β-catenin in response to fibroblast with collagen, we cells α2β1 integrin and cells with α2β1 integrin on polymerized collagen and and active β-catenin that the levels of (inactive) and active β-catenin high in cells with cells with α2β1 integrin these findings the IPF fibroblasts with collagen, low α2β1 integrin expression to activate PP2A, to levels of phosphorylated and high levels of active the of PP2A on GSK-3β we PP2A in control fibroblasts on collagen the PP2A of PP2A by the of phosphorylated GSK-3β in control fibroblasts and enhanced the of active β-catenin this we the of PP2A to the and the on the of Knockdown of in levels of phosphorylated GSK-3β in control fibroblasts these that low α2β1 integrin PP2A activity, which in levels of phosphorylated (inactive) the of PP2A in IPF to the on to of β1 integrin β1 integrin, of in IPF fibroblasts in a of that of the α2β1 is in IPF IPF fibroblasts with to fibroblast proliferation is by polymerized H. Raines E.W. Bornfeldt K.E. Roberts J.M. Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors.Cell. 1996; 87: 1069-1078Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar, 7Schor S.L. Cell proliferation and migration on collagen substrata in vitro.J Cell Sci. 1980; 41: 159-175Crossref PubMed Google Scholar, 8Rhudy R.W. McPherson J.M. Influence of the extracellular matrix on the proliferative response of human skin fibroblasts to serum and purified platelet-derived growth factor.J Cell Physiol. 1988; 137: 185-191Crossref PubMed Scopus (36) Google Scholar that of β1 integrin in control fibroblasts PP2A the of GSK-3β and the of active the of of β1 integrin on control fibroblast proliferation on polymerized collagen. Knockdown of β1 integrin a in the proliferation of control fibroblasts on polymerized collagen at with cells with control to in cell adhesion to the in β1 integrin we that PP2A is control fibroblasts with polymerized collagen and that this in levels of active we by and the on control fibroblast The proliferation of control fibroblasts in which by with cells with control indicate that a in β1 integrin PP2A levels control fibroblast proliferation on polymerized collagen, the of IPF fibroblasts on polymerized collagen. however, that of β1 integrin in IPF fibroblasts we to the of of β1 integrin on IPF fibroblast proliferation on collagen. Our indicate on collagen, control fibroblasts of active GSK-3β and their proliferation is to a with IPF that GSK-3β of β-catenin control fibroblast the of of GSK-3β by on control fibroblast proliferation on polymerized collagen. of GSK-3β by control fibroblast proliferation by with cells with control with of β1 integrin and the in control high levels of α2β1 integrin activate PP2A and the of active GSK-3β active Our that pathologically low α2β1 integrin in activation of the β-catenin proliferation and that high levels of β-catenin the ability of IPF fibroblasts to elude the proliferation-suppressive of polymerized collagen. this we β-catenin in IPF fibroblasts β-catenin and their proliferative ability on polymerized collagen. The of β-catenin in IPF fibroblasts with β-catenin with cells with control of β-catenin the proliferative capacity of IPF fibroblasts on polymerized collagen by with control the that activation of β-catenin by α2β1 integrin IPF fibroblast proliferation on collagen. The of IPF remains incompletely understood. An in IPF the unrelenting of the fibroproliferative for IPF that to the a fibroproliferative M. King T.E. A. Thoracic Respiratory of pulmonary fibrosis: and and for Med. PubMed Scopus Google Scholar, Idiopathic pulmonary fibrosis: Med. Full Text Full Text PDF PubMed Scopus Google Scholar, Idiopathic pulmonary fibrosis: and Med. Full Text Full Text PDF PubMed Scopus Google Scholar normal tissue after fibroproliferation is however, the fibroproliferative process to in of this disease and the of to on of this fibroproliferative to this progressive fibrotic we on the fibroproliferative process and on cellular the indicate that the IPF fibroblast a that features in with the fibroblast fibroblasts in and PubMed Scopus Google Scholar, F. F. G. J. C. S. H. E. C. R.G. fibroblasts with human J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, C. J. A. C. F. G. H. E. A. R.G. fibroblasts and suppressor for the response to PubMed Scopus Google Scholar, F. J.A. A. E. H. S. G. J.A. F. M. M. G. in fibroblasts suppresses PubMed Scopus Google Scholar that the IPF fibroblast, to low expression and low resulting in activation of the H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar, H. J. J. J. regulation of in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus (124) Google Scholar Our findings the that the IPF fibroblast has acquired a phenotype characterized by ability to proliferate in a type I collagen proliferation-suppressive that α2β1 integrin expression is abnormally in IPF fibroblasts and that this altered integrin these cells with their proliferative by and J. J. Integrin activation of protein phosphatase and of and kinase Cell Biol. PubMed Scopus Google Scholar cell adhesion to polymerized type I collagen, α2β1 integrin is a major collagen activation of the PP2A Here, we that low α2β1 integrin expression is a of the IPF fibroblast Our the that the in α2β1 integrin expression in IPF fibroblasts in a failure of the integrin to activate PP2A we IPF fibroblast with collagen, PP2A remains control fibroblasts with collagen, PP2A is with levels of β1 integrin of α2β1 by in control fibroblasts the ability of these cells to activate PP2A interacting with polymerized collagen, IPF fibroblast we demonstrate that which of to activate PP2A, cells with α2β1 activate PP2A in response to with polymerized collagen. to IPF cells activate PP2A, of α2β1 IPF however, cells proliferation on polymerized collagen, PP2A activity, their of α2β1 in a ability to to polymerized collagen. IPF fibroblasts to polymerized collagen of activation of the β-catenin demonstrate the ability to elude the proliferation-suppressive effects of polymerized collagen. PP2A is a phosphatase that has to and phosphatase a of Cell Biol. 2000; PubMed Scopus Google Scholar Our indicate that a major PP2A in IPF and control fibroblasts is as a PP2A phosphatase a of Cell Biol. 2000; PubMed Scopus Google Scholar that is abnormally in and the that IPF fibroblasts low PP2A H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar of a failure of the integrin to activate that this is the to of PP2A with in control and treatment of control fibroblasts with the PP2A the of indicate that low is for activation of the in IPF H. R. J. J. A. M. C. integrin signaling proliferation of lung fibroblasts patients with idiopathic pulmonary Med. PubMed Scopus Google Scholar the that GSK-3β is a major PP2A the of low PP2A phosphatase in IPF fibroblasts abnormally high of phosphorylated (inactive) GSK-3β resulting in high levels of β-catenin and proliferation of PP2A in control fibroblasts the levels of phosphorylated GSK-3β and and of integrin in control fibroblasts the of both GSK-3β and active Our findings indicate that integrin leads to a of integrin resulting in activation of the β-catenin pathway. we that IPF fibroblasts the proliferation-suppressive effects of polymerized collagen. to the of the altered on α2β1 expression and PP2A in with control we a to this in integrin expression and PP2A IPF and control fibroblasts and to the role of the in of β1 integrin, that the cells to collagen. the of in to the of integrin expression on proliferation, adhesion and as a that β1 integrin expression PP2A levels in of GSK-3β and levels of active as as ability of control fibroblasts to proliferate on polymerized collagen, IPF fibroblast we that the of β-catenin in IPF fibroblasts their ability to proliferate on polymerized collagen. that this integrin to the of this fibroproliferative for to the mechanism the pathologically low α2β1 integrin expression and activation in IPF to is abnormally low α2β1 integrin in the of integrin receptor is in matrix that to proliferation signaling remains at this An the of the IPF that IPF fibroblasts at cells that to to the lung the J.M. of in alveolar cells by growth role in idiopathic pulmonary fibrosis.Am J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, of fibrosis in the Scopus Google Scholar, and for fibrotic lung J Cell Physiol. PubMed Scopus Google Scholar, cell in pulmonary fibrosis and is by the extracellular PubMed Scopus Google Scholar, H. of fibroblasts to lung fibrosis.Am J Respir Crit Care Med. PubMed Scopus Google Scholar, V.J. C. of to the alveolar after fibrotic J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar, A. G. J. J. C. M. of in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. PubMed Scopus Google Scholar to the of IPF fibroblasts that this integrin of for the and β1 integrin with Integrin activation is in IPF with IPF and control fibroblasts on polymerized collagen. The of β1 integrin as a of by the with of integrin in IPF and control lung tissue of cells in IPF and control lung tissue for expression of integrin and β1 integrin in the tissue as a with of and β1 integrin is in cells IPF fibroblastic of and β1 integrin expression on IPF lung and on which of
Hong et al. (Sun,) studied this question.