G. Chandrasekher et al., HGF- and KGF-induced activation of PI-3K/p70 S6 kinase pathway in corneal epithelial cells: its relevance in wound healing, EXP EYE RES, 73(2), 2001, pp. 191-202
In this study we have investigated the involvement of PI-3K and its downstr
eam target p70 S6K in the signaling response of corneal epithelial cells af
ter HGF and KGF stimulation. HGF induced three- to fivefold increase in PI-
3K activity in 5-10 min, whereas KGF stimulation resulted in two- to three-
fold increase in activity in 2-10 min. Both growth factors also caused the
phosphorylation of p70 S6K and stimulation of its activity. HGF increased p
70 S6K activity by 300 % and KGF by about 200 %. Protein kinase C (PKC) act
ivator TPA also induced the phosphorylation of p70 S6K. Both the PI-3K inhi
bitor wortmannin and PKC inhibitor calphostin C blocked the phosphorylation
of p70 S6K mediated by the growth factors, However, the mitogen-activated
protein kinase (p42/44 MAPK) cascade inhibitor PD98059 had no effect on p70
S6K activation. Furthermore, HGF and KGF increased the rate of corneal epi
thelial wound healing in an organ culture model, and wortmannin and rapamyc
in (the p70 S6K inhibitor) blocked corneal epithelial wound healing promote
d by the growth factors. These studies suggest that PI-3K and p70 S6K are i
mportant signal transducers in the stimulation of corneal epithelial cells
by HGF and KGF. PKC is involved in the PI-3K-dependent activation of p70 S6
K but not MAPK. Inhibition of wound closure by PT-3K and p70 S6K inhibitors
suggests these enzymes play a significant role in corneal wound repair sti
mulated by HGF and K GF. (C) 2001 Academic Press.