title: Eukaryotic translation initiation factor 4E binding protein 1 (4EBP-1) function is suppressed by Src and protein phosphatase 2A (PP2A) on extracellular matrix.
abstract: Human lung fibroblasts utilize integrins to attach and proliferate on type I collagen. β1 integrin is the major integrin subunit for this attachment. Integrins coordinate cellular responses to cell-cell and cell-extracellular matrix interactions that regulate a variety of biological processes. Although β1 integrin-mediated signaling pathways in lung fibroblasts have been studied, a detailed molecular mechanism regulating translational control of gene expression by 4EBP-1 is not understood. 4EBP-1 inhibits cap-dependent translation by binding to the eIF4E translation initiation factor. We found that when lung fibroblasts attach to collagen via β1 integrin, high Src activity suppresses 4EBP-1 expression via PP2A, and the decrease of 4EBP-1 is due to protein degradation. The inhibition of Src activity dramatically increases PP2A and 4EBP-1 expression. Furthermore ectopic expression of PP2A, or PP2A silencing using PP2A siRNA confirmed that 4EBP-1 is regulated by PP2A. In addition, we found that 4EBP-1 inhibition by fibroblast attachment to collagen increases cap-dependent translation. Our study showed that when lung fibroblasts are attached to collagen matrix, the β1 integrin/Src/PP2A-mediated 4EBP-1 regulatory pathway is activated. We suggest that β1 integrin-mediated signaling pathway may be a crucial event in regulating fibroblast translational control machinery on collagen matrix.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA. nhoxx002@umn.edu
authors.forename: Richard Seonghun
authors.initials: RS
authors.lastname: Nho
authors.forename: Mark
authors.initials: M
authors.lastname: Peterson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins; D002460:Cell Line; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D019012:Integrin beta1; D010750:Phosphoproteins; D012315:RNA Caps; D019061:src-Family Kinases; D054648:Protein Phosphatase 2