Cell adhesion to fibronectin regulates membrane lipid biosynthesis through 5'-AMP-activated protein kinase.
We have shown that attachment to a fibronectin substrate stimulates two pathways of lipid biosynthesis in cultured human fibroblasts. Detachment of these cells (mechanically, with trypsin, or by RGDS peptides) caused a significant decrease in their 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and in their incorporation of [3H]acetate into fatty acids. This inhibition was substantially reversed by the reattachment of cells to fibronectin substrates, but not to poly-L-lysine substrates or to fibronectin in solution. Inhibiting phosphoprotein phosphatase activity with okadaic acid blocked the recovery of both biosynthetic activities. Both 3-hydroxy-3-methylglutaryl-coenzyme A reductase and fatty acid biosynthesis are known to be inhibited by the action of 5'-AMP-activated protein kinase, which is activated by an increase in the level of AMP relative to ATP. For example, in our system, sodium azide and 2-deoxy-D-glucose increased the ratio of cellular AMP to ATP and caused a decrease in lipid biosynthesis. We then verified the prediction that detachment of cells from substrates also caused an increase in the AMP/ATP ratio. We therefore conclude that the attachment of cells to fibronectin promotes lipid biosynthesis, presumably in coordination with the cellular growth response evoked by attachment to the extracellular matrix.
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Department of Biochemistry, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
Lange
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D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis; D002448:Cell Adhesion; D002478:Cells, Cultured; D005353:Fibronectins / Q000502:physiology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008563:Membrane Lipids / Q000096:biosynthesis*; D009097:Multienzyme Complexes / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases
D005353:Fibronectins; D008563:Membrane Lipids; D009097:Multienzyme Complexes; D009842:Oligopeptides; D019319:Okadaic Acid; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; C046617:arginyl-glycyl-aspartyl-serine; D006903:Hydroxymethylglutaryl CoA Reductases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases