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 language | English (US) |
|---|---|
| Pages (from-to) | 11127-11132 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 108 |
| Issue number | 27 |
| DOIs | |
| State | Published - Jul 5 2011 |
| Externally published | Yes |
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Keywords
- Myristoylation
- TKV interaction
ASJC Scopus subject areas
- General
Cite this
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 journal › Article
}
TY - JOUR
T1 - Smad inhibition by the Ste20 kinase misshapen
AU - Kaneko, Satoshi
AU - Chena, Xiaochu
AU - Lua, Peiyuan
AU - Yao, Xiaohao
AU - Wright, Theodore G.
AU - Rajurkar, Mihir
AU - Kariya, Ken Ichi
AU - Mao, Junhao
AU - Ip, Tony
AU - Xu, Lan
PY - 2011/7/5
Y1 - 2011/7/5
N2 - 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.
AB - 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.
KW - Myristoylation
KW - TKV interaction
UR - http://www.scopus.com/inward/record.url?scp=79960606073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960606073&partnerID=8YFLogxK
U2 - 10.1073/pnas.1104128108
DO - 10.1073/pnas.1104128108
M3 - Article
C2 - 21690388
AN - SCOPUS:79960606073
VL - 108
SP - 11127
EP - 11132
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 27
ER -