TAK1 MAPK Kinase Kinase Mediates Transforming Growth Factor-β Signaling by Targeting SnoN Oncoprotein for Degradation

Taisuke Kajino,Emily Omori,Shunsuke Ishii,Kunihiro Matsumoto,Jun Ninomiya-Tsuji

doi:10.1074/jbc.m700875200

Taisuke Kajino, Emily Omori + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m700875200

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Abstract

Transforming growth factor-beta (TGF-beta) regulates a variety of physiologic processes through essential intracellular mediators Smads. The SnoN oncoprotein is an inhibitor of TGF-beta signaling. SnoN recruits transcriptional repressor complex to block Smad-dependent transcriptional activation of TGF-beta-responsive genes. Following TGF-beta stimulation, SnoN is rapidly degraded, thereby allowing the activation of TGF-beta target genes. Here, we report the role of TAK1 as a SnoN protein kinase. TAK1 interacted with and phosphorylated SnoN, and this phosphorylation regulated the stability of SnoN. Inactivation of TAK1 prevented TGF-beta-induced SnoN degradation and impaired induction of the TGF-beta-responsive genes. These data suggest that TAK1 modulates TGF-beta-dependent cellular responses by targeting SnoN for degradation.

Highlights

Transforming growth factor-␤ (TGF-␤)[2] is a multifunctional cytokine involved in the regulation of proliferation, differentiation, migration, and survival of many different cell types (1, 2)
To study the role of TGF-␤-activated kinase 1 (TAK1) in TGF-␤ signaling, we screened for TAK1-binding proteins using the yeast two-hybrid system
These results suggest that TAK1 is involved in TGF-␤-dependent biological processes

Summary

Introduction

Transforming growth factor-␤ (TGF-␤)[2] is a multifunctional cytokine involved in the regulation of proliferation, differentiation, migration, and survival of many different cell types (1, 2). TGF-␤-induced nuclear accumulation of Smad2/3 was observed to be normal in cells expressing TAK1 siRNA. The accumulation of PAI-1 mRNA in response to TGF-␤ was impaired in the TAK1 siRNA-expressing cells (Fig. 3C). To determine whether the N terminus of SnoN is sufficient for TGF-␤-dependent degradation, we generated HaCaT cells stably expressing HA-tagged SnoN-(1–366).

Results

Conclusion