The PLC-PKC cascade is required for IL-1beta-dependent Erk and Akt activation: their role in proliferation.

We investigated the signaling mechanisms that lead to IL-1beta-induced cell proliferation. Treatment of Balb 3T3 cells with IL-1beta activated two signaling pathways, Erk and Akt. IL-1beta also increased tyrosine phosphorylation of PLC-gamma in Src kinase-dependent manner. Pharmacological inhibition of the PLC-PKC cascade by using specific inhibitor for PLC-gamma (U73122) and PKC (GFX) strongly inhibited IL-1beta-induced Erk and Akt activation. Inhibition of MEK1 by its specific inhibitor, PD98059 substantially inhibited Erk activation. Similarly, inhibition of PI3K activation by its specific inhibitor LY294002 suppressed Akt phosphorylation. Moreover, IL-1beta-induced association of PLC-gamma with SHPS-1. SHPS-1 mutants lacking the tyrosine phosphorylation sites failed to associate with PLC-gamma. Finally, IL-1beta-induced proliferation of Balb 3T3 cells and inhibition of Erk and Akt signalings or their upstream signaling molecules, Src kinase and PKC by their inhibitors strongly inhibited IL-1beta-dependent cell proliferation. Taken together, our results suggest that a SHPS-1-PLC-gamma complex activate the PLC-PKC cascade, which is required for the activation of IL-1beta-dependent Erk and Akt signalings and cell proliferation.