Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex

Abstract : The protein kinase TAK1, which has been implicated in the activation of MAP kinase cascades and the production of inflammatory mediators by lipopolysaccharide (LPS), interleukin 1 (IL-1) and tumour necrosis factor (TNF), comprises the catalytic subunit complexed to the regulatory subunits, turned TAK1-binding subunit 1 (TAB1) and either TAB2 or TAB3. We previously identified a feedback control mechanism by which p38α MAP kinase down-regulates TAK1 and showed that p38α MAP kinase phosphorylates TAB1 at Ser423 and Thr431. Here, we identify two IL-1-stimulated phosphorylation sites on TAB2 (Ser372 and Ser524) and three on TAB3 (Ser60, Thr404 and Ser506) in human IL-1R cells and mouse embryonic fibroblasts (MEFs). Ser372 and Ser524 of TAB2 are not phosphorylated by pathways dependent on p38α/β MAP kinases, ERK1/2 and JNK1/2. In contrast, Ser60 and Thr404 of TAB3 appear to be phosphorylated directly by p38α MAPK, while Ser506 is phosphorylated by MAPKAP-K2/MAPKAP-K3, which are protein kinases activated by p38α MAPK. Studies using TAB1-/- MEFs indicate important roles for TAB1 in recruiting p38α MAPK to the TAK1 complex for the phosphorylation of TAB3 at Ser60 and Thr404 and to inhibit the dephosphorylation of TAB3 at Ser506. TAB1 is also required to induce TAK1 catalytic activity, since neither IL-1 nor TNFα were able stimulate detectable TAK1 activity in TAB1-deficient MEFs. Surprisingly, the IL-1 and TNFα-stimulated activation of MAP kinase cascades and IκB kinases were similar in TAB1-/-, MEKK3-/- and wild type MEFs, suggesting that another MAP3K may mediate the IL-1/TNFα-induced activation of these signaling pathways in TAB1-/- and MEKK3-/- MEFs.
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Heidi Mendoza, David G Campbell, Kerry Burness, James Hastie, Natalia Ronkina, et al.. Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochemical Journal, Portland Press, 2007, 409 (3), pp.711-722. ⟨10.1042/BJ20071149⟩. ⟨hal-00478877⟩

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