BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo

Gopal P Sapkota , Felicity S Newell , Christopher Armstrong , Jennifer Bain , Morten Frodin , Matthias Grauert , Matthias Hoffmann , Gisela Schnapp , Martin Steegmaier , Philip Cohen , Dario R Alessi (1)

1 School of Life Sciences

Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of protein kinase A (PKA), protein kinase B (PKB also known as Akt), protein kinase C (PKC), p70 ribosomal S6 kinase (S6K), p90 ribosomal S6 kinase (RSK) and the mitogen and stress activated protein kinase (MSK), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC 50} of 10-30 nM, but does not significantly inhibit 9 other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeable and prevents the phorbol ester and EGF-induced phosphorylation of GSK3{beta} and LKB1 in 293 and Rat-2 cells, which are mediated by RSK. In contrast, BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester or EGF-induced phosphorylation of CREB, consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.

Mots clés: Life Sciences

Gopal P Sapkota, Felicity S Newell, Christopher Armstrong, Jennifer Bain, Morten Frodin, et al.. BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochemical Journal, 2006, 401 (1), pp.29-38. ⟨10.1042/BJ20061088⟩. ⟨hal-00478634⟩