Cargando…

Docking interactions of the JNK scaffold protein WDR62

JNK (c-Jun N-terminal kinase) is part of a MAPK (mitogen-activated protein kinase) signalling cascade. Scaffold proteins simultaneously associate with various components of the MAPK signalling pathway and play a crucial role in signal transmission and MAPK regulation. WDR62 (WD repeat domain 62) is...

Descripción completa

Detalles Bibliográficos
Autores principales: Cohen-Katsenelson, Ksenya, Wasserman, Tanya, Khateb, Samer, Whitmarsh, Alan J., Aronheim, Ami
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462610/
https://www.ncbi.nlm.nih.gov/pubmed/21749326
http://dx.doi.org/10.1042/BJ20110284
_version_ 1782245185022853120
author Cohen-Katsenelson, Ksenya
Wasserman, Tanya
Khateb, Samer
Whitmarsh, Alan J.
Aronheim, Ami
author_facet Cohen-Katsenelson, Ksenya
Wasserman, Tanya
Khateb, Samer
Whitmarsh, Alan J.
Aronheim, Ami
author_sort Cohen-Katsenelson, Ksenya
collection PubMed
description JNK (c-Jun N-terminal kinase) is part of a MAPK (mitogen-activated protein kinase) signalling cascade. Scaffold proteins simultaneously associate with various components of the MAPK signalling pathway and play a crucial role in signal transmission and MAPK regulation. WDR62 (WD repeat domain 62) is a JNK scaffold protein. Recessive mutations within WDR62 result in severe cerebral cortical malformation. In the present study we demonstrate the association of WDR62 with endogenous and overexpressed proteins of both JNK2 and the JNK2-activating kinase MKK7 (MAPK kinase 7). Association of WDR62 with JNK2 and MKK7 occurs via direct protein–protein interactions. We mapped the docking domain of WDR62 responsible for the association with JNK. WDR62 interacts with all JNK isoforms through a D domain motif located at the C-terminus. A WDR62 mutant lacking the putative JNK-binding domain fails to activate and recruit JNK to cellular granules. Furthermore, a synthetic peptide composed of the WDR62 docking domain inhibits JNK2 activity in vitro. WDR62 association with JNK2 requires both the JNK CD and ED domains, and the binding requisite is distinct from that of the previously described JNK2 association with JIP1 (JNK-interacting protein 1). Next, we characterized the association between WDR62 and MKK7. WDR62 associates directly with the MKK7β1 isoform independently of JNK binding, but fails to interact with MKK7α1. Furthermore, MKK7β1 recruits a protein phosphatase that dephosphorylates WDR62. Interestingly, a premature termination mutation in WDR62 that results in severe brain developmental defects does not abrogate WDR62 association with either JNK or MKK7. Therefore such mutations represent a loss of WDR62 function independent of JNK signalling.
format Online
Article
Text
id pubmed-3462610
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Portland Press Ltd.
record_format MEDLINE/PubMed
spelling pubmed-34626102012-10-12 Docking interactions of the JNK scaffold protein WDR62 Cohen-Katsenelson, Ksenya Wasserman, Tanya Khateb, Samer Whitmarsh, Alan J. Aronheim, Ami Biochem J Research Article JNK (c-Jun N-terminal kinase) is part of a MAPK (mitogen-activated protein kinase) signalling cascade. Scaffold proteins simultaneously associate with various components of the MAPK signalling pathway and play a crucial role in signal transmission and MAPK regulation. WDR62 (WD repeat domain 62) is a JNK scaffold protein. Recessive mutations within WDR62 result in severe cerebral cortical malformation. In the present study we demonstrate the association of WDR62 with endogenous and overexpressed proteins of both JNK2 and the JNK2-activating kinase MKK7 (MAPK kinase 7). Association of WDR62 with JNK2 and MKK7 occurs via direct protein–protein interactions. We mapped the docking domain of WDR62 responsible for the association with JNK. WDR62 interacts with all JNK isoforms through a D domain motif located at the C-terminus. A WDR62 mutant lacking the putative JNK-binding domain fails to activate and recruit JNK to cellular granules. Furthermore, a synthetic peptide composed of the WDR62 docking domain inhibits JNK2 activity in vitro. WDR62 association with JNK2 requires both the JNK CD and ED domains, and the binding requisite is distinct from that of the previously described JNK2 association with JIP1 (JNK-interacting protein 1). Next, we characterized the association between WDR62 and MKK7. WDR62 associates directly with the MKK7β1 isoform independently of JNK binding, but fails to interact with MKK7α1. Furthermore, MKK7β1 recruits a protein phosphatase that dephosphorylates WDR62. Interestingly, a premature termination mutation in WDR62 that results in severe brain developmental defects does not abrogate WDR62 association with either JNK or MKK7. Therefore such mutations represent a loss of WDR62 function independent of JNK signalling. Portland Press Ltd. 2011-10-13 2011-11-01 /pmc/articles/PMC3462610/ /pubmed/21749326 http://dx.doi.org/10.1042/BJ20110284 Text en © 2011 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Cohen-Katsenelson, Ksenya
Wasserman, Tanya
Khateb, Samer
Whitmarsh, Alan J.
Aronheim, Ami
Docking interactions of the JNK scaffold protein WDR62
title Docking interactions of the JNK scaffold protein WDR62
title_full Docking interactions of the JNK scaffold protein WDR62
title_fullStr Docking interactions of the JNK scaffold protein WDR62
title_full_unstemmed Docking interactions of the JNK scaffold protein WDR62
title_short Docking interactions of the JNK scaffold protein WDR62
title_sort docking interactions of the jnk scaffold protein wdr62
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462610/
https://www.ncbi.nlm.nih.gov/pubmed/21749326
http://dx.doi.org/10.1042/BJ20110284
work_keys_str_mv AT cohenkatsenelsonksenya dockinginteractionsofthejnkscaffoldproteinwdr62
AT wassermantanya dockinginteractionsofthejnkscaffoldproteinwdr62
AT khatebsamer dockinginteractionsofthejnkscaffoldproteinwdr62
AT whitmarshalanj dockinginteractionsofthejnkscaffoldproteinwdr62
AT aronheimami dockinginteractionsofthejnkscaffoldproteinwdr62