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PMID: 10856237 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1.

The EMBO journal ·Vol. 19 ·No. 12 ·2000-06-15 ·Pages 2924-34

Frödin M, Jensen CJ, Merienne K, Gammeltoft S

Abstract

The 90 kDa ribosomal S6 kinase-2 (RSK2) is a growth factor-stimulated protein kinase with two kinase domains. The C-terminal kinase of RSK2 is activated by ERK-type MAP kinases, leading to autophosphorylation of RSK2 at Ser386 in a hydrophobic motif. The N-terminal kinase is activated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) through phosphorylation of Ser227, and phosphorylates the substrates of RSK. Here, we identify Ser386 in the hydrophobic motif of RSK2 as a phosphorylation-dependent docking site and activator of PDK1. Treatment of cells with growth factor induced recruitment of PDK1 to the Ser386-phosphorylated hydrophobic motif and phosphorylation of RSK2 at Ser227. A RSK2-S386K mutant showed no interaction with PDK1 or phosphorylation at Ser227. Interaction with Ser386-phosphorylated RSK2 induced autophosphorylation of PDK1. Addition of a synthetic phosphoSer386 peptide (RSK2(373-396)) increased PDK1 activity 6-fold in vitro. Finally, mutants of RSK2 and MSK1, a RSK-related kinase, with increased affinity for PDK1, were constitutively active in vivo and phosphorylated histone H3. Our results suggest a novel regulatory mechanism based on phosphoserine-mediated recruitment of PDK1 to RSK2, leading to coordinated phosphorylation and activation of PDK1 and RSK2.

MeSH Terms
3-Phosphoinositide-Dependent Protein Kinases Animals Binding Sites Catalysis Enzyme Activation Humans Mice Mitogen-Activated Protein Kinases/genetics,metabolism Models, Biological Mutation Phosphorylation Protein Binding Protein Serine-Threonine Kinases/metabolism Protein Structure, Tertiary Ribosomal Protein S6 Kinases Ribosomal Protein S6 Kinases, 90-kDa Serine
Chemicals
Serine 3-Phosphoinositide-Dependent Protein Kinases PDPK1 protein, human Pdpk1 protein, mouse Protein Serine-Threonine Kinases Ribosomal Protein S6 Kinases Ribosomal Protein S6 Kinases, 90-kDa mitogen and stress-activated protein kinase 1 ribosomal protein S6 kinase, 90kDa, polypeptide 3 Mitogen-Activated Protein Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Frödin M
Department of Clinical Biochemistry, Glostrup Hospital, DK-2600 Glostrup, Denmark. mf@dcb-glostrup.dk
Jensen C J
Merienne K
Gammeltoft S
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.12.2924
Email
mf@dcb-glostrup.dk
Published
2000-06-15
Pages
2924-34
Language
English
Region
England
NLM ID
8208664
PMCID
PMC203368
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/19.12.2924 PMC Full Text View journal details
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