IκB Kinase γ/Nuclear Factor-κB-Essential Modulator (IKKγ/NEMO) Facilitates RhoA GTPase Activation, which, in Turn, Activates Rho-associated Kinase (ROCK) to Phosphorylate IKKβ in Response to Transforming Growth Factor (TGF)-β1
Open accessAbstract
Transforming growth factor (TGF)-β1 plays several roles in a variety of cellular functions. TGF-β1 transmits its signal through Smad transcription factor-dependent and -independent pathways. It was reported that TGF-β1 activates NF-κB and RhoA, and RhoA activates NF-κB in several kinds of cells in a Smad-independent pathway. However, the activation molecular mechanism of NF-κB by RhoA upon TGF-β1 has not been clearly elucidated. We observed that RhoA-GTP level was increased by TGF-β1 in RAW264.7 cells. RhoA-GDP and RhoGDI were bound to N- and C-terminal domains of IKKγ, respectively. Purified IKKγ facilitated GTP binding to RhoA complexed with RhoGDI. Furthermore, Dbs, a guanine nucletotide exchange factor of RhoA much more enhanced GTP binding to RhoA complexed with RhoGDI in the presence of IKKγ. Indeed, si-IKKγ abolished RhoA activation in response to TGF-β1 in cells. However, TGF-β1 stimulated the release of RhoA-GTP from IKKγ and Rho-associated kinase (ROCK), an active RhoA effector protein, directly phosphorylated IKKβ in vitro, whereas TGF-β1-activated kinase 1 activated RhoA upon TGF-β1 stimulation. Taken together, our data indicate that IKKγ facilitates RhoA activation via a guanine nucletotide exchange factor, which in turn activates ROCK to phosphorylate IKKβ, leading to NF-κB activation that induced the chemokine expression and cell migration upon TGF-β1.
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RhoA signaling can mediate actin-independent gene transcription such as the ROCK-mediated activation of NF-κB through phosphorylation of IKKβ.
“RhoA signaling can mediate actin-independent gene transcription such as the ROCK-mediated activation of the proinflammatory transcription factor NF-кB through phosphorylation of the IкB kinase subunit β (IKKβ), as described above [39].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [39]
The Results and Discussion report that RhoA/ROCK signaling promotes NF-κB activation and that ROCK directly phosphorylates IKKβ in vitro. The Discussion contrasts this pathway with actin-linked SRF activation, but the paper does not establish that NF-κB-dependent transcription is actin-independent. (LLM, conf=0.84)
Experimental — accuracy not yet measuredActivated IKKβ phosphorylates IκB, leading to its degradation and release of NF-κB that translocates to the nucleus and activates transcription of proinflammatory factors.
“Activated IKKβ then phosphorylates the inhibitor of NF-кB (IкB), leading to its degradation and release of NF-кB that translocates to the nucleus and activates transcription of proinflammatory factors [39].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [39]
ROCK activates the proinflammatory transcription factor NF-κB through phosphorylation of IKKβ.
“ROCK activates the proinflammatory transcription factor NF-кB through phosphorylation of the IкB kinase subunit β (IKKβ).”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [39]
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Molecular basis for Rac2 regulation of phagocyte NADPH oxidase
Diebold, B. A., & Bokoch, G. M. (2001) · Nature Immunology · doi:10.1038/85259 · Cited by 318 · see citing works
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Upstream regulators and downstream effectors of NF-κB in Alzheimer’s disease
Shi, Z.-M., Han, Y.-W., Han, X.-H., Zhang, K., Chang, Y.-N., Hu, Z.-M., Qi, H.-X., Ting, C., Zhen, Z., & Hong, W. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.05.022 · Cited by 125 · see citing works
RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
- Authors
- Kim, H.-J., Kim, J.-G., Moon, M.-Y., Park, S.-H., & Park, J.-B.
- Affiliations
- Hallym University (KR)
- Corresponding author
- Park, Seol-Hye
- Park, Jae-Bong
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 289
- Issue
- 3
- Pages
- 1429-1440
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3894326
- OpenAlex
- W2060862744
- Cited by
- 46
- References
- 1
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 3 · 2014: 1
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- RhoA activation, Rho kinase, TGF-β1 signaling, NF-κB activation, IKKβ phosphorylation, RhoGDI, guanine nucleotide exchange factor, chemokine expression, cell migration, RAW 264.7 macrophages
- MeSH terms
- Animals, Cell Line, Cell Movement, Enzyme Activation, Gene Expression Regulation, Humans, Phosphorylation, NF-kappa B, Protein Structure, Tertiary, Chemokines, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, Intracellular Signaling Peptides and Proteins, Mice, I-kappa B Kinase, Transforming Growth Factor beta1, rho-Associated Kinases, rho Guanine Nucleotide Dissociation Inhibitor alpha
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