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

123 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
Number of pages12
JournalCell
Volume133
Issue number3
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

Fingerprint

Phosphotransferases
Cell signaling
Genes
Crosstalk
Gene Components
Proteasome Endopeptidase Complex
Protein Kinases
Transcription Factors
Complementary DNA
Genome
Screening
Degradation

Keywords

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

Cite this

Varjosalo, M., Björklund, M., Cheng, F., Syvänen, H., Kivioja, T., Kilpinen, S., ... 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
Varjosalo, Markku ; Björklund, Mikael ; Cheng, Fang ; Syvänen, Heidi ; Kivioja, Teemu ; Kilpinen, Sami ; Sun, Zairen ; Kallioniemi, Olli ; Stunnenberg, Hendrik G. ; He, Wei-Wu ; Ojala, Päivi ; Taipale, Jussi. / Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling. In: Cell. 2008 ; Vol. 133, No. 3. pp. 537-548.
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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.",
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author = "Markku Varjosalo and Mikael Bj{\"o}rklund and Fang Cheng and Heidi Syv{\"a}nen and Teemu Kivioja and Sami Kilpinen and Zairen Sun and Olli Kallioniemi and Stunnenberg, {Hendrik G.} and Wei-Wu He and P{\"a}ivi Ojala and Jussi Taipale",
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Varjosalo, M, Björklund, M, Cheng, F, Syvänen, H, Kivioja, T, Kilpinen, S, Sun, Z, Kallioniemi, O, Stunnenberg, HG, He, W-W, Ojala, P & Taipale, J 2008, 'Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling', Cell, vol. 133, no. 3, pp. 537-548. https://doi.org/10.1016/j.cell.2008.02.047

Application of Active and Kinase-Deficient Kinome Collection for Identification of Kinases Regulating Hedgehog Signaling. / Varjosalo, Markku; Björklund, Mikael; Cheng, Fang; Syvänen, Heidi; Kivioja, Teemu; Kilpinen, Sami; Sun, Zairen; Kallioniemi, Olli; Stunnenberg, Hendrik G.; He, Wei-Wu; Ojala, Päivi (Corresponding Author); Taipale, Jussi (Corresponding Author).

In: Cell, Vol. 133, No. 3, 2008, p. 537-548.

Research output: Contribution to journalArticleScientificpeer-review

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

PY - 2008

Y1 - 2008

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.

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KW - cellular signaling

KW - protein kinases

KW - kinases

KW - genes

KW - gene cloning

KW - gene expression

U2 - 10.1016/j.cell.2008.02.047

DO - 10.1016/j.cell.2008.02.047

M3 - Article

VL - 133

SP - 537

EP - 548

JO - Cell

JF - Cell

SN - 0092-8674

IS - 3

ER -