ERK (extracellular-signal-regulated kinase) 4 [MAPK (mitogen-activated protein kinase) 4] and ERK3 (MAPK6) are atypical MAPKs. One major difference between these proteins and the classical MAPKs is substitution of the conserved T-X-Y motif within the activation loop by a single phospho-acceptor site within an S-E-G motif. In the present study we report that Ser186 of the S-E-G motif in ERK4 is phosphorylated in vivo. Kinase-dead ERK4 is also phosphorylated on Ser186, indicating that an ERK4 kinase, rather than autophosphorylation, is responsible. Co-expression of MK5 [MAPK-activated protein kinase 5; also known as PRAK (p38-regulated/activated kinase)], a physiological target of ERK4, increases phosphorylation of Ser186. This is not dependent on MK5 activity, but does require interaction between ERK4 and MK5 suggesting that MK5 binding either prevents ERK4 dephosphorylation or facilitates ERK4 kinase activity. ERK4 mutants in which Ser186 is replaced with either an alanine residue or a phospho-mimetic residue (glutamate) are unable to activate MK5 and Ser186 is also required for cytoplasmic anchoring of MK5. Both defects seem to reflect an impaired ability of the ERK4 mutants to interact with MK5. We find that there are at least two endogenous pools of wild-type ERK4. One form exhibits reduced mobility when analysed using SDS/PAGE. This is due to MK5-dependent phosphorylation and only this retarded ERK4 species is both phosphorylated on Ser186 and co-immunoprecipitates with wild-type MK5. We conclude that binding between ERK4 and MK5 facilitates phosphorylation of Ser186 and stabilization of the ERK4–MK5 complex. This results in phosphorylation and activation of MK5, which in turn phosphorylates ERK4 on sites other than Ser186 resulting in the observed mobility shift.
Skip Nav Destination
Article navigation
May 2008
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
April 14 2008
The Ser186 phospho-acceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5
Maria Perander;
Maria Perander
*Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
Search for other works by this author on:
Espen Åberg;
Espen Åberg
*Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
Search for other works by this author on:
Bjarne Johansen;
Bjarne Johansen
*Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
Search for other works by this author on:
Bo Dreyer;
Bo Dreyer
*Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
Search for other works by this author on:
Ingrid J. Guldvik;
Ingrid J. Guldvik
*Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
Search for other works by this author on:
Heidi Outzen;
Heidi Outzen
†Department of Biochemistry, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
Search for other works by this author on:
Stephen M. Keyse;
Stephen M. Keyse
‡Cancer Research UK Stress Response Laboratory, Biomedical Research Centre, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY, U.K.
Search for other works by this author on:
Ole-Morten Seternes
Ole-Morten Seternes
1
*Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway
1To whom correspondence should be addressed (email olems@fagmed.uit.no).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
October 08 2007
Revision Received:
December 04 2007
Accepted:
February 05 2008
Accepted Manuscript online:
February 05 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 411 (3): 613–622.
Article history
Received:
October 08 2007
Revision Received:
December 04 2007
Accepted:
February 05 2008
Accepted Manuscript online:
February 05 2008
Citation
Maria Perander, Espen Åberg, Bjarne Johansen, Bo Dreyer, Ingrid J. Guldvik, Heidi Outzen, Stephen M. Keyse, Ole-Morten Seternes; The Ser186 phospho-acceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5. Biochem J 1 May 2008; 411 (3): 613–622. doi: https://doi.org/10.1042/BJ20071369
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.