Transforming Growth Factor-β (TGF-β1) Activates TAK1 via TAB1-mediated Autophosphorylation, Independent of TGF-β Receptor Kinase Activity in Mesangial Cells

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine that signals through the interaction of type I (T beta RI) and type II (T beta RII) receptors to activate distinct intracellular pathways. TAK1 is a serine/threonine kinase that is rapidly activated by TGF-beta 1. However, the molecular mechanism of TAK1 activation is incompletely understood. Here, we propose a mechanism whereby TAK1 is activated by TGF-beta 1 in primary mouse mesangial cells. Under unstimulated conditions, endogenous TAK1 is stably associated with T beta RI. TGF-beta 1 stimulation causes rapid dissociation from the receptor and induces TAK1 phosphorylation. Deletion mutant analysis indicates that the juxtamembrane region including the GS domain of T beta RI is crucial for its interaction with TAK1. Both T beta RI-mediated TAK1 phosphorylation and TGF-beta 1-induced TAK1 phosphorylation do not require kinase activity of T beta RI. Moreover, T beta RI-mediated TAK1 phosphorylation correlates with the degree of its association with T beta RI and requires kinase activity of TAK1. TAB1 does not interact with TGF-beta receptors, but TAB1 is indispensable for TGF-beta 1-induced TAK1 activation. We also show that TRAF6 and TAB2 are required for the interaction of TAK1 with T beta RI and TGF-beta 1-induced TAK1 activation in mouse mesangial cells. Taken together, our data indicate that TGF-beta 1-induced interaction of T beta RI and T beta RII triggers dissociation of TAK1 from T beta RI, and subsequently TAK1 is phosphorylated through TAB1-mediated autophosphorylation and not by the receptor kinase activity of T beta RI.