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, Jussi Taipale

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

150 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)537-548
Aantal pagina's12
TijdschriftCell
Volume133
Nummer van het tijdschrift3
DOI's
StatusGepubliceerd - 2 mei 2008
Extern gepubliceerdJa

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