Regulation of the Interleukin-1-induced Signaling Pathways by a Novel Member of the Protein Phosphatase 2C Family (PP2Cε)

Protein Phosphatase 6 Down-regulates TAK1 Kinase Activation in the IL-1 Signaling Pathway

“…In general, the level of protein phosphorylation is controlled by the balanced activities of protein kinases and protein phosphatases. Indeed, TAK1 activity is known to be regulated by protein phosphatase PP2C family members in the unstimulated state (24,25). In this study, we found that inhibition of type 2A protein phosphatases results in hyperphosphorylation and hyperactivation of TAK1 in response to IL-1 stimulation.…”

“…The mechanism by which TAK1 is down-regulated has not yet been elucidated, but it is likely to involve protein phosphatases. Indeed, both TAK1 phosphorylation and activation are regulated by PP2C family (also known as MPP) phosphatases, which participate in silencing TAK1 basal activity in the unstimulated state (24,25). To further address which protein phosphatases reverse stimuliinduced TAK1 activation, we examined the effects of protein phosphatase inhibitors on IL-1-induced TAK1 phosphorylation.…”

Activation Mechanism of c-Jun Amino-terminal Kinase in the Course of Neural Differentiation of P19 Embryonic Carcinoma Cells

“…We have recently reported that PP2C⑀, a member of protein phosphatase 2C family, inactivated the SAPK signaling pathway by selectively associating with and dephosphorylating TAK1 (24). PP2C⑀ gave no influence on the phosphorylation levels of the downstream components of TAK1 such as MKK4 and JNK.…”

“…However, the upstream signaling pathway responsible for the activation of JNK in the course of the neutral differentiation has not been elucidated. Here, we present evidence indicating that activity levels of MKK4 and TAK1 are enhanced in the neurally differentiating cells and that expression of protein phosphatase 2C⑀ (PP2C⑀), an inactivator of TAK1 (24), inhibits the neural differentiation. Although TAK1, phospho-MKK4, and phospho-JNK were localized in both the nuclei and the neurites of the neurally differentiating cells, two adapter proteins involved in the activation of TAK1 were differently localized, suggesting that two TAK1-MKK4-JNK signaling pathways are independently activated at the different intracellular locations and may participate in the regulation of the neural differentiation of P19 cells.…”

Toll-Like Receptors in Health and Disease: Complex Questions Remain

“…This may in part be achieved by the increased expression of inhibitory molecules, such as the inhibitor of signaling, IRAK-M (61), or the association of Tollip with the signaling complex, preventing IRAK activation (62). Unsurprisingly for a kinase-regulated system, investigations of IL-1 signaling suggest that relatively specific phosphatases may participate in signaling deactivation (63). Suppressor of cytokine signaling 1, a member of the suppressor of cytokine signaling family that suppresses the JAK-STAT signaling cascade activated by proteins such as IFN-␥, also reduces NF-B activation by LPS and appears to be involved in TLR4 homologous desensitization (64).…”