The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions

Stefanie Ritterhoff, Carla M. Farah, Julia Grabitzki, Günter Lochnit, Alexander Skurat, Michael Lienhard Schmitz

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Protein kinases are organized in hierarchical networks that are assembled and regulated by scaffold proteins. Here, we identify the evolutionary conserved WD40-repeat protein Han11 as an interactor of the kinase homeodomain- interacting protein kinase 2 (HIPK2). In vitro experiments showed the direct binding of Han11 to HIPK2, but also to the kinases DYRK1a, DYRK1b and mitogen-activated protein kinase kinase kinase 1 (MEKK1). Han11 was required to allow coupling of MEKK1 to DYRK1 and HIPK2. Knockdown experiments in Caenorhabditis elegans showed the relevance of the Han11 orthologs Swan-1 and Swan-2 for the osmotic stress response. Downregulation of Han11 in human cells lowered the threshold and amplitude of HIPK2- and MEKK1-triggered signalling events and changed the kinetics of kinase induction. Han11 knockdown changed the amplitude and time dependence of HIPK2-driven transcription in response to DNA damage and also interfered with MEKK1-triggered gene expression and stress signalling. Impaired signal transmission also occurred upon interference with stoichiometrically assembled signalling complexes by Han11 overexpression. Collectively, these experiments identify Han11 as a novel scaffold protein regulating kinase signalling by HIPK2 and MEKK1.

Original languageEnglish
Pages (from-to)3750-3761
Number of pages12
JournalEMBO Journal
Volume29
Issue number22
DOIs
StatePublished - Nov 17 2010

Fingerprint

MAP Kinase Kinase Kinase 1
MAP Kinase Kinase Kinases
Homeodomain Proteins
Scaffolds (biology)
Protein Kinases
Proteins
Phosphotransferases
Experiments
Transcription
Gene expression
Scaffolds
Osmoregulation
Cells
hematopoietic progenitor kinase 1
WD40 Repeats
Caenorhabditis elegans
Kinetics
DNA Damage
DNA
Down-Regulation

Keywords

  • Han11
  • HIPK2
  • MAP kinase
  • MEKK1
  • scaffold protein

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions. / Ritterhoff, Stefanie; Farah, Carla M.; Grabitzki, Julia; Lochnit, Günter; Skurat, Alexander; Schmitz, Michael Lienhard.

In: EMBO Journal, Vol. 29, No. 22, 17.11.2010, p. 3750-3761.

Research output: Contribution to journalArticle

Ritterhoff, Stefanie ; Farah, Carla M. ; Grabitzki, Julia ; Lochnit, Günter ; Skurat, Alexander ; Schmitz, Michael Lienhard. / The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions. In: EMBO Journal. 2010 ; Vol. 29, No. 22. pp. 3750-3761.
@article{9cf91bee3f6f4e7dbb86394c476b14e2,
title = "The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions",
abstract = "Protein kinases are organized in hierarchical networks that are assembled and regulated by scaffold proteins. Here, we identify the evolutionary conserved WD40-repeat protein Han11 as an interactor of the kinase homeodomain- interacting protein kinase 2 (HIPK2). In vitro experiments showed the direct binding of Han11 to HIPK2, but also to the kinases DYRK1a, DYRK1b and mitogen-activated protein kinase kinase kinase 1 (MEKK1). Han11 was required to allow coupling of MEKK1 to DYRK1 and HIPK2. Knockdown experiments in Caenorhabditis elegans showed the relevance of the Han11 orthologs Swan-1 and Swan-2 for the osmotic stress response. Downregulation of Han11 in human cells lowered the threshold and amplitude of HIPK2- and MEKK1-triggered signalling events and changed the kinetics of kinase induction. Han11 knockdown changed the amplitude and time dependence of HIPK2-driven transcription in response to DNA damage and also interfered with MEKK1-triggered gene expression and stress signalling. Impaired signal transmission also occurred upon interference with stoichiometrically assembled signalling complexes by Han11 overexpression. Collectively, these experiments identify Han11 as a novel scaffold protein regulating kinase signalling by HIPK2 and MEKK1.",
keywords = "Han11, HIPK2, MAP kinase, MEKK1, scaffold protein",
author = "Stefanie Ritterhoff and Farah, {Carla M.} and Julia Grabitzki and G{\"u}nter Lochnit and Alexander Skurat and Schmitz, {Michael Lienhard}",
year = "2010",
month = "11",
day = "17",
doi = "10.1038/emboj.2010.251",
language = "English",
volume = "29",
pages = "3750--3761",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "22",

}

TY - JOUR

T1 - The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions

AU - Ritterhoff, Stefanie

AU - Farah, Carla M.

AU - Grabitzki, Julia

AU - Lochnit, Günter

AU - Skurat, Alexander

AU - Schmitz, Michael Lienhard

PY - 2010/11/17

Y1 - 2010/11/17

N2 - Protein kinases are organized in hierarchical networks that are assembled and regulated by scaffold proteins. Here, we identify the evolutionary conserved WD40-repeat protein Han11 as an interactor of the kinase homeodomain- interacting protein kinase 2 (HIPK2). In vitro experiments showed the direct binding of Han11 to HIPK2, but also to the kinases DYRK1a, DYRK1b and mitogen-activated protein kinase kinase kinase 1 (MEKK1). Han11 was required to allow coupling of MEKK1 to DYRK1 and HIPK2. Knockdown experiments in Caenorhabditis elegans showed the relevance of the Han11 orthologs Swan-1 and Swan-2 for the osmotic stress response. Downregulation of Han11 in human cells lowered the threshold and amplitude of HIPK2- and MEKK1-triggered signalling events and changed the kinetics of kinase induction. Han11 knockdown changed the amplitude and time dependence of HIPK2-driven transcription in response to DNA damage and also interfered with MEKK1-triggered gene expression and stress signalling. Impaired signal transmission also occurred upon interference with stoichiometrically assembled signalling complexes by Han11 overexpression. Collectively, these experiments identify Han11 as a novel scaffold protein regulating kinase signalling by HIPK2 and MEKK1.

AB - Protein kinases are organized in hierarchical networks that are assembled and regulated by scaffold proteins. Here, we identify the evolutionary conserved WD40-repeat protein Han11 as an interactor of the kinase homeodomain- interacting protein kinase 2 (HIPK2). In vitro experiments showed the direct binding of Han11 to HIPK2, but also to the kinases DYRK1a, DYRK1b and mitogen-activated protein kinase kinase kinase 1 (MEKK1). Han11 was required to allow coupling of MEKK1 to DYRK1 and HIPK2. Knockdown experiments in Caenorhabditis elegans showed the relevance of the Han11 orthologs Swan-1 and Swan-2 for the osmotic stress response. Downregulation of Han11 in human cells lowered the threshold and amplitude of HIPK2- and MEKK1-triggered signalling events and changed the kinetics of kinase induction. Han11 knockdown changed the amplitude and time dependence of HIPK2-driven transcription in response to DNA damage and also interfered with MEKK1-triggered gene expression and stress signalling. Impaired signal transmission also occurred upon interference with stoichiometrically assembled signalling complexes by Han11 overexpression. Collectively, these experiments identify Han11 as a novel scaffold protein regulating kinase signalling by HIPK2 and MEKK1.

KW - Han11

KW - HIPK2

KW - MAP kinase

KW - MEKK1

KW - scaffold protein

UR - http://www.scopus.com/inward/record.url?scp=78449296172&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78449296172&partnerID=8YFLogxK

U2 - 10.1038/emboj.2010.251

DO - 10.1038/emboj.2010.251

M3 - Article

VL - 29

SP - 3750

EP - 3761

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 22

ER -