A potential role for extracellular signal-regulated kinases in prostaglandin F-2 alpha-induced protein synthesis in smooth muscle cells

To understand the mechanisms of prostaglandin F-2 alpha (PGF(2 alpha))-indu ced protein synthesis in vascular smooth muscle cells (VSMC), we have studi ed its effect on two major signal transduction pathways: mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI3-kinase) and their do wnstream targets ribosomal protein S6 kinase (p70(S6k)) and eukaryotic init iation factor eIF4E and its regulator 4E-BP1, PGF(2 alpha) induced the acti vities of extracellular signal-regulated kinase 2 (ERK2) and Jun N-terminal kinase 1 (JNK1) groups of mitogen-activated protein kinases, PI3-kinase, a nd p70(S6k) in a time-dependent manner in growth-arrested VSMC. PGF(2 alpha ) also induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis, and basic fibroblast growth factor-a (bFGF-2) expression in VSMC, Whereas i nhibition of PI3-kinase by wortmannin completely blocked the p70(S6k) activ ation, it only partially decreased the ERK2 activity, and had no significan t effect on global protein synthesis and bFGF-2 expression induced by PGF(2 alpha), Rapamycin, a potent inhibitor of p70(S6k), also failed to prevent PGF(2 alpha)-induced global protein synthesis and bFGF-2 expression, althou gh it partially decreased ERK2 activity. In contrast, inhibition of ERK2 ac tivity by PD 098059 led to a significant loss of PGF(2 alpha)-induced eIF4E and 4E-BP1 phosphorylation, global protein synthesis, and bFGF-2 expressio n. PGF(2 alpha)-induced phosphorylation of eIF4E and 4E-BP1 was also found to be sensitive to inhibition by both wortmannin and rapamycin, These findi ngs demonstrate that 1) PI3-kinase-dependent and independent mechanisms app ear to be involved in PGF(2 alpha)-induced activation of ERK2; 2) PGF(2 alp ha)-induced eIF4E and 4E-BP1 phosphorylation appear to be mediated by both ERK-dependent and PI3-kinase-dependent rapamycin-sensitive mechanisms; and 3) ERK-dependent eIF4E phosphorylation but not PIS-kinase-dependent p70S6k activation correlates with PGF(2 alpha)-induced global protein synthesis an d bFGF-2 expression in VSMC.