TY - JOUR
T1 - Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling
AU - Varjosalo, Markku
AU - Björklund, Mikael
AU - Cheng, Fang
AU - Syvänen, Heidi
AU - Kivioja, Teemu
AU - Kilpinen, Sami
AU - Sun, Zairen
AU - Kallioniemi, Olli
AU - Stunnenberg, Hendrik G.
AU - He, Wei Wu
AU - Ojala, Päivi
AU - Taipale, Jussi
N1 - Funding Information:
We thank Drs. P. A. Beachy, R. Toftgård, P. ten Dijke, S.-P. Li, and J. Vieira for reagents; Dr. K. Koli for help with the TGFβ assay; J. Lahdenperä for lab automation; P. Jansen for LC/MS; Dr. A. Vaahtokari for microscopy; and Drs. T. Mäkelä, J. Keski-Oja, P. Salven, M. Taipale, J. Thompson, M. Wolf, and O. Hallikas for critical review of the manuscript. The work was supported by the Finnish Academy Translational Genome-Scale Biology Center of Excellence, EU FP6 project Tumorhost Genomics, Biocentrum Helsinki, the University of Helsinki, the Sigrid Juselius Foundation, and the Finnish Cancer Research Organizations.
PY - 2008/5/2
Y1 - 2008/5/2
N2 - 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.
AB - 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.
KW - PROTEINS
KW - SIGNALING
KW - SYSBIO
UR - http://www.scopus.com/inward/record.url?scp=43049142654&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2008.02.047
DO - 10.1016/j.cell.2008.02.047
M3 - Article
C2 - 18455992
AN - SCOPUS:43049142654
SN - 0092-8674
VL - 133
SP - 537
EP - 548
JO - Cell
JF - Cell
IS - 3
ER -