beta1-Integrin-collagen interaction suppresses FoxO3a by the coordination of Akt and PP2A.
When cells attach to the extracellular matrix (ECM) a proliferation permissive signal is engaged. The mechanism involves activation of the integrin/PI3K/Akt signal pathway. FoxO3a is a transcriptional activator and inhibits cell proliferation via up-regulating the expression of the cell cycle inhibitor p27. Furthermore, it is known that activated Akt can suppress FoxO3a function. However, it is not known whether integrin interaction with the ECM regulates FoxO3a function. We examined whether the beta1-integrin-mediated signaling pathway promotes fibroblast proliferation via FoxO3a suppression. We found that when fibroblasts are attached to collagen, PTEN protein expression and activity are inhibited due to promotion of PTEN degradation. This decrease in PTEN function permits FoxO3a suppression via the PI3K/Akt pathway. In contrast, the inhibition of PI3K/Akt or reconstitution of PTEN restores FoxO3a expression on collagen. Furthermore, we found that the serine/threonine phosphatase PP2A also regulates FoxO3a. PP2A expression/activity is low when fibroblasts are attached to collagen, and PP2A overexpression augments FoxO3a levels. Thus the mechanism involves a coordinated decrease in PTEN and PP2A phosphatase activity and increase in PI3K/Akt activity. We show that beta1-integrin-ECM interaction decreases FoxO3a protein levels via caspase-3-mediated cleavage. Our novel finding indicates that during fibroblast interaction with ECM, activation of beta1-integrin/PI3K/Akt by inhibiting PTEN in combination with low PP2A phosphatase activity synergistically inhibits FoxO3a, promoting fibroblast proliferation.
Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA. nhoxx002@umn.edu
Richard Seonghun
RS
Nho
Judy
J
Kahm
D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D024042:Collagen Type I; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D019012:Integrin beta1; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D051059:PTEN Phosphohydrolase; D053148:Caspase 3