Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling

Markku Varjosalo, Mikael Björklund, Fang Cheng, Heidi Syvänen, Teemu Kivioja, Sami Kilpinen, Zairen Sun, Olli Kallioniemi, Hendrik G. Stunnenberg, Wei-Wu He, Päivi Ojala (Corresponding Author), Jussi Taipale (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

151 Citations (Scopus)

Abstract

To allow genome-scale identification of genes that regulate cellular signaling, we cloned >90% of all human full-length protein kinase cDNAs and constructed the corresponding kinase activity-deficient mutants. To establish the utility of this resource, we tested the effect of expression of the kinases on three different cellular signaling models. In all screens, many kinases had a modest but significant effect, apparently due to crosstalk between signaling pathways. However, the strongest effects were found with known regulators and novel components, such as MAP3K10 and DYRK2, which we identified in a mammalian Hedgehog (Hh) signaling screen. DYRK2 directly phosphorylated and induced the proteasome-dependent degradation of the key Hh pathway-regulated transcription factor, GLI2. MAP3K10, in turn, affected GLI2 indirectly by modulating the activity of DYRK2 and the known Hh pathway component, GSK3β. Our results establish kinome expression screening as a highly effective way to identify physiological signaling pathway components and genes involved in pathological signaling crosstalk.
Original languageEnglish
Pages (from-to)537-548
JournalCell
Volume133
Issue number3
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

Keywords

  • signaling
  • proteins
  • sysbio
  • cellular
  • cellular signaling
  • protein kinases
  • kinases
  • genes
  • gene cloning
  • gene expression

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