Arachidonic acid activates mitogen-activated protein (MAP) kinase-activated protein kinase 2 and mediates adhesion of a human breast carcinoma cell line to collagen type IV through a p38 MAP kinase-dependent pathway

Adhesion of metastatic human mammary carcinoma MDA-MB-435 cells to the base ment membrane protein collagen type TV can be activated by treatment with a rachidonic acid. We initially observed that this arachidonic acid-mediated adhesion was inhibited by the tyrosine kinase inhibitor genistein, Therefor e, we examined the role of the mitogen-activated protein (MAP) kinase famil y tyrosine phosphorylation-regulated pathways in arachidonic acid-stimulate d cell adhesion. Arachidonic acid stimulated the phosphorylation of p38, th e activation of MAP kinase-activated protein kinase 2 (MAPKAPK2, a downstre am substrate of p38), and the phosphorylation of heat shock protein 27 (a d ownstream substrate of MAP kinase-activated protein kinase 2), Treatment wi th the p38 inhibitor PD169316 completely and specifically inhibited arachid onic acid-mediated cell adhesion to collagen type TV. p38 activity was spec ifically associated with arachidonic acid-stimulated adhesion; this was dem onstrated by the observation that 12-O-tetradecanoylphorbol 13-acetate-acti vated cell adhesion was not blocked by inhibiting p38 activity. Extracellul ar signal-regulated protein kinases (ERKs) 1 and 2 were also activated by a rachidonic acid; however, cell adhesion to collagen type TV was not highly sensitive to PD98059, an inhibitor of MAP kinase kinase/ERK kinase 1 (MEK1) that blocks activation of the ERKs. c-Jun NH2-terminal kinase was not acti vated by arachidonic acid treatment of these cells. Together, these data su ggest a novel role for p38 MAP kinase in regulating adhesion of breast canc er cells to collagen type IV.