Arachidonic Acid Signals Spreading and Migration

Abstract

As cells interact with substrates and engage their integrins, several signaling cascades are initiated, including one involving eicosanoids [leukotrienes (LTs) and prostaglandins (PGs)] produced from metabolism of arachidonic acid (AA). Stockton and Jacobson studied signals produced from AA during cell spreading and then migration. A biphasic AA signal was seen in cells plated on fibronectin, with the first increase important for cell spreading and the second sustained increase important for cell migration. Pharmacological agents were used to modulate AA production and metabolism. Treatment of cells with these agents demonstrated that spreading was dependent on metabolism of AA to LTs produced from the activity of 5-lipoxygenase (5-LOX) and could be mimicked by the addition of LTB4. Inhibition of the cyclooxygenase (COX) metabolic pathway led to increased cell surface area, suggesting that COX activity may help to terminate the cell spreading signal. A connection between AA metabolism by COX and the extracellular signal-regulated kinases ERK1 and ERK2 was uncovered using an inhibitor of these enzymes. Inhibition of COX or ERKs promoted cell spreading and inhibited cell migration, both of which could be reversed by exogenous application of PGE 2 . Kinetic analysis of the activity of the LOX, ERKs, and COX suggests the following order of events after integrin engagement: AA accumulates and then is metabolized by LOX to produce a cell spreading signal; ERK is also activated early in the process, which stimulates the expression of inducible COX-2; increased COX activity decreases the AA pool for LOX metabolism to terminate cell spreading and produces PGs needed for cell migration. R. A. Stockton, B. S. Jacobson, Modulation of cell-substrate adhesion by arachidonic acid: Lipoxygenase regulates cell spreading and ERK1/2-inducible cyclooxygenase regulates cell migration in NIH-3T3 cells. Mol. Biol. Cell 12 , 1937-1956 (2001). [Abstract] [Full Text]