Smad inhibition by the Ste20 kinase Misshapen.

Article Details


Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, Kariya K, Mao J, Ip YT, Xu L

Smad inhibition by the Ste20 kinase Misshapen.

Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11127-32. doi: 10.1073/pnas.1104128108. Epub 2011 Jun 20.

PubMed ID
21690388 [ View in PubMed

The level of TGF-beta/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-beta/BMP is blocked by a highly conserved phosphorylation event in the alpha-helix 1 region of Smad [T312 in Drosophila Smad1 (MAD)]. alpha-helix 1 phosphorylation reduces Smad interaction with TGF-beta/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 alpha-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.

DrugBank Data that Cites this Article

NameUniProt ID
TRAF2 and NCK-interacting protein kinaseQ9UKE5Details
Mitogen-activated protein kinase kinase kinase kinase 4O95819Details
Misshapen-like kinase 1Q8N4C8Details