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 V. Skurat, Michael Lienhard Schmitz

Research output: Contribution to journalArticle

40 Scopus citations

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

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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)

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