Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Wen, Y. et al.

Evidence that 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid activates p21-activated kinase.

The effect of 12-hydroxyeicosatetraenoic acid (12-HETE), an arachidonic acid metabolite of 12-lipoxygenase, to activate p21(Rac/Cdc42)-activated kinase ( PAK1) was studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type-1a angiotensin II receptor (CHO-AT(1a)). 12-HETE (0.1 microM) treatment induced a time-dependent activation of PAK1, with a peak effect at 10 min (335 +/- 16% of control; n=3, P<0.001). The stimulatory effect of 12-HETE on PAK1 activity was dose-dependent, with the maximal activation at 0.01 microM (350+/-15% of control; n=3, P<0.001). A PAK1 fragment encoding the Cdc42/Rac binding domain (amino acid residues 67-150 of hPAK1 termed PBD), was transfected into CHO-AT(1a) cells. PBD transfection markedly reduced 12-HETE-induced PAK1 activation. Furthermore, transfection of dominant negative Cdc42 and Rac1 inhibited 12-HETE- induced PAK1, strongly suggesting that Cdc42 and Rac1 are the upstream activators of 12-HETE- induced PAK1 activation. Low concentrations (1.5 microM) of LY294002, a highly specific inhibitor of phosphoinositide 3-kinase ( PI-3K), abolished 12-HETE-induced PAK1 activation, suggesting that PI-3K activation is upstream of 12-HETE- induced PAK1 activation. Transfection of dominant negative PAK1 blocked 12-HETE-induced PAK1, cJun N-terminal kinase (JNK1) and extracellular-signal-regulated kinase ( ERK) activity, while transfection of constitutively active PAK1 stimulated PAK1, JNK1 and ERK activity, suggesting that PAK1 is an upstream activator of 12-HETE- induced JNK1 and ERK activation in these cells. We conclude that 12-HETE can activate Cdc42, Rac1 and PI-3K, which then participate as upstream signalling molecules for PAK1 and JNK1 activation.[1]

References

Evidence that 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid activates p21-activated kinase. Wen, Y., Gu, J., Knaus, U.G., Thomas, L., Gonzales, N., Nadler, J.L. Biochem. J. (2000) [Pubmed]

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