Arachidonic acid signaling to the cytoskeleton: the role of cyclooxygenase and cyclic AMP-dependent protein kinase in actin bundling.
Cell adhesion to the extracellular matrix via integrins is a primary regulatory mechanism for numerous aspects of normal cellular function. However, disruption of this interaction can result in pathology. For example, one characteristic of transformed cells is loss of adhesion dependence for viability. Adhesion also is a necessary step in tumor metastasis. It has been shown previously, in HeLa cells, that cell attachment to a gelatin-coated substrate results in the release of arachidonic acid, which is metabolized by lipoxygenase. A subsequent cascade of lipid second messengers activates protein kinase C, which triggers actin polymerization leading to cell spreading. We now demonstrate by inhibitor studies and biochemical analysis, a parallel branch of arachidonic acid signaling that reorganizes the actin cytoskeleton into small bundles. This branch of the pathway is initiated by cyclooxygenase, which generates prostaglandins and causes the downstream activation of cyclic AMP-dependent protein kinase. This work elucidates a system of interacting signals in which arachidonic acid functions at a branch point in cytoskeletal signaling. The lipoxygenase branch provides polymerized actin; these actin filaments act as a substrate for the cylooxygenase branch to generate actin bundles.
Glenn
Honor L
HL
Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, 01003, USA.
Jacobson
Bruce S
BS
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D022502:Stress Fibers / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000199:Actins; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D005576:Colforsin; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate