A direct interaction between TGFβ activated kinase 1 and the TGFβ type II receptor:: Implications for TGFβ signalling and cardiac hypertrophy

Objective: Transforming growth factor beta (TGF)-activated kinase 1 (TAK1) is a MAP kinase kinase kinase involved in numerous signalling pathways and is strongly implicated in cardiac hypertrophy and heart failure. TGF is also associated with hypertension and heart disease, and evidence suggests that TGF beta 1 and TAK1 act together in a cardiac stress signalling pathway. Canonical TGF[ signalling is mediated through Smad transcription factors, but TGF beta can also rapidly activate TAK1. The activation of the Smad cascade is well characterised, but little is known about how TAK1 is activated in response to TGF beta, and no direct link between any MAPK kinase pathway and the TGF beta receptors has yet been established. Since TAK1 is activated by TGF beta within 1 min in cardiomyocytes, we hypothesised there might be a direct interaction between TAK1 and one of the TGF beta receptors. Methods: We used a combination of in vitro binding assays and co-immunoprecipitation (IP) experiments to investigate whether TAK1 interacted with the type 1 (ALK1 or ALK5) or type II (TBRII) TGF beta receptors. Interactions between endogenous proteins were tested using mouse myoblast and rat cardiomyocyte cells. Results: Immunoprecipitation and in vitro binding assays show that TAK1 binds directly to TBRII. Precipitation of endogenous TAK1 protein in rat cardiomyocytes shows that, in addition to a direct association with TBRII, it also interacts indirectly with ALK5. Conclusions: We describe a novel and specific interaction between TAK1 and TBRII which, for the first time, directly links TAK1 to the TGF beta signalling cascade and potentially explains how TGF beta signalling in cardiomyocytes mediates a hypertrophic response. (C) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.