2. Insulin signalling.
For many years, we studied the structure-function relationships and regulation by protein phosphorylation of the PFK-2/fructose-2,6-bisphosphatase isozymes. We showed that insulin stimulated heart glycolysis via PFK-2 activation and that protein kinase B (PKB) could phosphorylate and activate heart PFK-2.
Protein kinases of the insulin signalling pathway downstream of PDK1 that converge on heart PFK-2
Phosphoinositide-dependent protein kinase-1 (PDK1) is part of the cascade mediating the effect of insulin to activate heart PFK-2. To understand insulin action downstream of PDK1, we studied the role of SGK3 (serum- and glucocorticoid-regulated protein kinase-3) in insulin action in perfused rat hearts and in HEK 293T cells. Heart PFK-2 can be phosphorylated by SGK3 in vitro leading to its activation. However, co-transfection of HEK 293T cells with SGK3 siRNA did not affect insulin-induced PFK-2 activation. SGK3 is therefore not required for heart PFK-2 activation by insulin. Our previous results using a dominant-negative PKB in HEK293 transfections suggested that PKB did not participate in heart PFK-2 activation by insulin. However, in HEK293 cells co-transfected with heart PFK-2 and total PKB siRNA, insulin-induced PFK-2 activation was abrogated. Our results with PKBβ-knockout mice indicate that this isoform is not required for heart PFK-2 activation by insulin. Studies on the role of PKBα by siRNA knock-down indicate that this isoform likely mediates insulin-induced heart PFK-2 activation.
To know more... (pdf chapter of the last de Duve Institute report)
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