BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoformsin vitroandin vivo

Abstract

Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), 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 signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. 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 (cAMP-response-element-binding protein), consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.

Phosphorylation of Eukaryotic Translation Initiation Factor 4B (EIF4B) by Open Reading Frame 45/p90 Ribosomal S6 Kinase (ORF45/RSK) Signaling Axis Facilitates Protein Translation during Kaposi Sarcoma-associated Herpesvirus (KSHV) Lytic Replication

“…5C), suggesting that RSK activity is required for the phosphorylation during KSHV lytic replication. Because ORF45 is phosphorylated efficiently by RSKs (17), a shift in electrophoretic mobility of ORF45 attested to effective inhibition of RSK activity by BI-D1870, although no apparent change in phosphorylation of RSKs was observed as reported previously (54). These experiments confirmed that KSHV lytic replication induces rapamycin and U0126 doubly insensitive eIF4B phosphorylation that requires RSK activity.…”

Excessive Na+/H+ Exchange in Disruption of Dendritic Na+ and Ca2+ Homeostasis and Mitochondrial Dysfunction following in Vitro Ischemia

“…FMK blocks the ␣ 1 -adrenoceptermediated NHE-1 phosphorylation and stimulation in rat ventricular myocytes (29). On the other hand, BI-D1870 has been shown to be a potent ATP-competitive inhibitor of all p90 RSK isoforms (20). In this study, we found that FMK and BI-D1870 were equally effective in inhibiting OGD/REOX-mediated NHE-1 activation, implying a role for p90 RSK isoforms 1 and 2.…”

Angiotensin II regulates phosphorylation of actin‐associated proteins in human podocytes

“…In contrast, the RSK inhibitor used in this study directly inhibited RSK kinase activity without influencing AngII-induced phosphorylation of RSK (Fig. 3A) (41).…”