Fig. 4

TLR-initiated signaling and the involved protein Ser/Thr phosphatases (Figs 3, 4). Summary of serine and threonine phosphorylation and de-phosphorylation events in TLR-signaling. IRAK1 phosphorylation by IRAK4 is reverted by PP2A. TRAF6 activity is inhibited by PP1 and PP4. TAK-1 has multiple phosphorylation sites, which are targeted by PP1 (Ser-432), PP6 (Thr-187), PPM1B (Ser-192), PPM1F (Thr-187), PPM1L (Thr-187), and PPM1M (unknown residues). PP1-mediated inactivation of TAK1 occurs in four sequential steps (Top frame on left). GADD34 binds to phosphorylated TAK1 (1), and recruits PP1C (2). The TAK1-GADD34-PP1C complex is formed (3) and PP1C catalyses TAK1 dephosphorylation and inactivation (4). Subsequently, the NEMO-IKK⍺/β complex phosphorylation by TAK1 is reverted by PPM1A, PPM1B, PPM1L and PPM1M on residues Ser-177 and Ser-181 and by PP1 on Ser-180/Ser-181. In the ground state, NEMO-IKKα/β complex is in a non-phosphorylated inactive form associated with GADD34/CUEDC2/PP1C (Lower frame on left). Upon stimulation, the NEMO-IKKα/β complex is released from PP1C by TRAF6 recruiment (1), IKKα and IKKβ are phosphorylated by TAK1 and subsequently trigger degradation of IκBα (2). CUEDC2 is recruited to phosphorylated IKKα/β (3), recruits GADD34 (4) and GADD34 in turn recruits PP1C (5). Finally, PP1C dephosphorylates IKKα/β and the whole complex retunrs to the ground state (6). The phosphorylation of IκBα is countered by PP6. NF-κB is de-phosphorylated by PP1, PP4 (Thr-465) and PPM1D (Ser-536). Tyrosine, serine and threonine residues are represented by white, green and red circles, respectively. Dephosphorylation is indicated by a red stop line, activation (ubiquitination or phosphorylation) and translocation are indicated by plain and dashed arrows, respectively