Abstract
The P70 ribosomal protein S6 kinase 1 (P70S6K1) is activated by the mammalian target of rapamycin (mTORC1) and regulates proliferation, growth, and metabolism. PF-4708671 is a novel, cell-permeable, has been proposed to be a highly specific inhibitor of p70S6K1. It is used in micromolar concentration range to dissect signaling pathways downstream of mTORC1 and to study the function of p70S6K1. Here we show that PF-4708671 induces AMP-activated protein kinase (AMPK) phosphorylation and activation in immortalized mouse embryonic fibroblasts (MEF) independently of p70S6K1, due to specific inhibition of mitochondrial respiratory chain Complex I.
Highlights
IntroductionP70 ribosomal protein S6 kinases (p70S6K) 1 & 2 (S6K1, S6k2) are two isoforms of the AGC kinase (protein kinase A/protein kinase G/protein kinase C) family
P70 ribosomal protein S6 kinases (p70S6K) 1 & 2 (S6K1, S6k2) are two isoforms of the AGC kinase family
With P70S6K1 inhibition, added PF-4708671 resulted in dose-dependent phosphorylation of AMPK(Thr172) and its ACC(Ser79) downstream substrate to an extent similar to that induced by oligomycin (Figure 1A)
Summary
P70 ribosomal protein S6 kinases (p70S6K) 1 & 2 (S6K1, S6k2) are two isoforms of the AGC kinase (protein kinase A/protein kinase G/protein kinase C) family. P70S6K isoforms are activated by the phosphorylation of Thr389 catalyzed by the rapamycin-sensitive mammalian TOR complex 1 (mTORC1) [2,3,4,5]. PF-4708671 inhibits p70S6K1 at mid nanomolar concentrations (IC50 of 160 nM). In a panel of ,90 protein and lipid kinases of most closely related AGC family members, PF4708671 was found to be highly selective for p70S6K1, being 400fold less potent for inhibiting S6K2. Among the AGC kinase family, mitogen- and stressactivated protein kinase 1 (MSK1) was found to be the most sensitive to PF-470867, with an IC50 of 950 nM in vitro.
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