Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling

Markku Varjosalo (Lead / Corresponding author), Mikael Bjorklund (Lead / Corresponding author), Fang Cheng, Heidi Syvanen, Teemu Kivioja, Sami Kilpinen, Zairen Sun, Olli Kallioniemi, Hendrik G. Stunnenberg, Wei-Wu He, Paivi Ojala (Lead / Corresponding author), Jussi Taipale (Lead / Corresponding author)

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    129 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, GSK3b. 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
    Number of pages12
    JournalCell
    Volume133
    Issue number3
    DOIs
    Publication statusPublished - 2 May 2008

    Keywords

    • Protein kinase
    • Kaposis sarcoma
    • Transcriptional activity
    • Cubitus interruptus
    • DNA sequences
    • Human genome
    • MEK kinase
    • 1 gene
    • Activation
    • Pathway

    Cite this

    Varjosalo, M., Bjorklund, M., Cheng, F., Syvanen, H., Kivioja, T., Kilpinen, S., Sun, Z., Kallioniemi, O., Stunnenberg, H. G., He, W-W., Ojala, P., & Taipale, J. (2008). Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell, 133(3), 537-548. https://doi.org/10.1016/j.cell.2008.02.047