Smad inhibition by the Ste20 kinase misshapen

Satoshi Kaneko, Xiaochu Chena, Peiyuan Lua, Xiaohao Yao, Theodore G. Wright, Mihir Rajurkar, Ken Ichi Kariya, Junhao Mao, Tony Ip, Lan Xu

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The level of TGF-β/bone morphogenetic protein (BMP) signaling through Smad is tightly regulated to ensure proper embryonic patterning and homeostasis. Here we show that Smad activation by TGF-β/BMP is blocked by a highly conserved phosphorylation event in the α-helix 1 region of Smad [T312 in Drosophila Smad1 (MAD)]. α-helix 1 phosphorylation reduces Smad interactionwith TGF-β/BMP receptor kinase and affects all receptor-activated Smads except Smad3. Tissue culture and transgenic studies in Drosophila further demonstrate that the biological activity of MAD is repressed by T312 phosphorylation in vivo. Through RNAi screening of the kinome,we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation. Targeted expression of an active form of Msn in the wing imaginal disk disrupted activation of endogenous MAD by Dpp and expression of the Dpp/MAD target gene. Msn kinases belong to the Ste20 kinase family that has been shown to act as MAP kinase kinase kinase kinase (MAP4K). Our findings thus reveal a function of Msn independent of its impact on MAP kinase cascades. This Smad inhibition mechanism by Msn likely has important implications for development and disease.

Original languageEnglish (US)
Pages (from-to)11127-11132
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number27
DOIs
StatePublished - Jul 5 2011
Externally publishedYes

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Phosphotransferases
Phosphorylation
Bone Morphogenetic Proteins
Drosophila
Bone Morphogenetic Protein Receptors
Imaginal Discs
MAP Kinase Kinase Kinases
MAP Kinase Signaling System
RNA Interference
Protein Kinases
Homeostasis
mycophenolic adenine dinucleotide
Genes

Keywords

  • Myristoylation
  • TKV interaction

ASJC Scopus subject areas

  • General

Cite this

Kaneko, S., Chena, X., Lua, P., Yao, X., Wright, T. G., Rajurkar, M., ... Xu, L. (2011). Smad inhibition by the Ste20 kinase misshapen. Proceedings of the National Academy of Sciences of the United States of America, 108(27), 11127-11132. https://doi.org/10.1073/pnas.1104128108

Smad inhibition by the Ste20 kinase misshapen. / Kaneko, Satoshi; Chena, Xiaochu; Lua, Peiyuan; Yao, Xiaohao; Wright, Theodore G.; Rajurkar, Mihir; Kariya, Ken Ichi; Mao, Junhao; Ip, Tony; Xu, Lan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 27, 05.07.2011, p. 11127-11132.

Research output: Contribution to journalArticle

Kaneko, S, Chena, X, Lua, P, Yao, X, Wright, TG, Rajurkar, M, Kariya, KI, Mao, J, Ip, T & Xu, L 2011, 'Smad inhibition by the Ste20 kinase misshapen', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 27, pp. 11127-11132. https://doi.org/10.1073/pnas.1104128108
Kaneko, Satoshi ; Chena, Xiaochu ; Lua, Peiyuan ; Yao, Xiaohao ; Wright, Theodore G. ; Rajurkar, Mihir ; Kariya, Ken Ichi ; Mao, Junhao ; Ip, Tony ; Xu, Lan. / Smad inhibition by the Ste20 kinase misshapen. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 27. pp. 11127-11132.
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