PUBLICATION
Transforming Growth Factor (TGF)-β-activated Kinase 1 (TAK1) Activation Requires Phosphorylation of Serine 412 by Protein Kinase A Catalytic Subunit α (PKACα) and X-linked Protein Kinase (PRKX)
- Authors
- Ouyang, C., Nie, L., Gu, M., Wu, A., Han, X., Wang, X., Shao, J., Xia, Z.
- ID
- ZDB-PUB-140717-3
- Date
- 2014
- Source
- The Journal of biological chemistry 289(35): 24226-37 (Journal)
- Registered Authors
- Keywords
- IL-1R, NF-kappa B (NF-KB), TAK1, inflammation, innate immunity, mitogen-activated protein kinase (MAPK), protein kinase A (PKA), serine/threonine protein kinase, toll-like receptor (TLR), tumor necrosis factor (TNF)
- MeSH Terms
-
- Cell Line
- Mutagenesis, Site-Directed
- Humans
- Phosphorylation
- Dimerization
- Catalytic Domain
- MAP Kinase Kinase Kinases/genetics
- MAP Kinase Kinase Kinases/metabolism*
- Cyclic AMP-Dependent Protein Kinases/chemistry
- Cyclic AMP-Dependent Protein Kinases/metabolism*
- Amino Acid Sequence
- Sequence Homology, Amino Acid
- Animals
- Enzyme Activation
- Molecular Sequence Data
- Protein Serine-Threonine Kinases/metabolism*
- Mice
- Zebrafish
- PubMed
- 25028512 Full text @ J. Biol. Chem.
Citation
Ouyang, C., Nie, L., Gu, M., Wu, A., Han, X., Wang, X., Shao, J., Xia, Z. (2014) Transforming Growth Factor (TGF)-β-activated Kinase 1 (TAK1) Activation Requires Phosphorylation of Serine 412 by Protein Kinase A Catalytic Subunit α (PKACα) and X-linked Protein Kinase (PRKX). The Journal of biological chemistry. 289(35):24226-37.
Abstract
TGF-β-activated kinase 1 (TAK1) is a key kinase in mediating toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) signaling. Although TAK1 activation involves the phosphorylation of Thr184 and Thr187 residues at the activation loop, the molecular mechanism underlying the complete activation of TAK1 remains elusive. In this work, we show that the Thr187 phosphorylation of TAK1 is regulated by its C-terminal coiled-coil domain mediated dimerization in an autophosphorylation manner. Importantly, we find that TAK1 activation in mediating downstream signaling requires an additional phosphorylation at serine 412 (Ser412), which is critical for TAK1 response to proinflammatory stimuli, such as tumor necrosis factor (TNF)-α, lipopolysaccharide (LPS), and IL-1β. In vitro kinase and short hairpin RNA-based knockdown assays reveal that TAK1 Ser412 phosphorylation is regulated by cAMP-dependent protein kinase catalytic subunit α (PKACα) and X-linked protein kinase (PRKX), which is essential for proper signaling and proinflammatory cytokine induction by TLR/IL-1R activation. Morpholino-based in vivo knockdown and rescue studies show that the corresponding site Ser391 in zebrafish TAK1 plays a conserved role in nuclear factor-κB activation. Collectively, our data unravel a previously unknown mechanism involving TAK1 phosphorylation mediated by PKACα and PRKX that contributes to innate immune signaling.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping