Abstract
Originalsprog | Engelsk |
---|---|
Tidsskrift | Biochemical Journal |
Vol/bind | 401 |
Udgave nummer | 1 |
Sider (fra-til) | 29-38 |
Antal sider | 9 |
ISSN | 0264-6021 |
DOI | |
Status | Udgivet - 2007 |
Bibliografisk note
Keywords: Animals; Cell Line; Chromones; Enzyme Activation; Enzyme Inhibitors; Humans; Isoenzymes; Kinetics; Morpholines; Protein Kinase Inhibitors; Pteridines; Rats; Ribosomal Protein S6 Kinases, 90-kDaAdgang til dokumentet
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BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. / Sapkota, Gopal P; Cummings, Lorna; Newell, Felicity S; Armstrong, Christopher; Bain, Jennifer; Frödin, Morten; Grauert, Matthias; Hoffmann, Matthias; Schnapp, Gisela; Steegmaier, Martin; Cohen, Philip; Alessi, Dario R.
I: Biochemical Journal, Bind 401, Nr. 1, 2007, s. 29-38.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
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TY - JOUR
T1 - BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo.
AU - Sapkota, Gopal P
AU - Cummings, Lorna
AU - Newell, Felicity S
AU - Armstrong, Christopher
AU - Bain, Jennifer
AU - Frödin, Morten
AU - Grauert, Matthias
AU - Hoffmann, Matthias
AU - Schnapp, Gisela
AU - Steegmaier, Martin
AU - Cohen, Philip
AU - Alessi, Dario R
N1 - Keywords: Animals; Cell Line; Chromones; Enzyme Activation; Enzyme Inhibitors; Humans; Isoenzymes; Kinetics; Morpholines; Protein Kinase Inhibitors; Pteridines; Rats; Ribosomal Protein S6 Kinases, 90-kDa
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
U2 - 10.1042/BJ20061088
DO - 10.1042/BJ20061088
M3 - Journal article
C2 - 17040210
VL - 401
SP - 29
EP - 38
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 1
ER -