Role of transglutaminase II in retinoic acid-induced activation of RhoA-associated kinase-2
Open accessAbstract
Transamidation is a post-translational modification of proteins mediated by tissue transglutaminase II (TGase), a GTP-binding protein, participating in signal transduction pathways as a non-conventional G-protein. Retinoic acid (RA), which is known to have a role in cell differentiation, is a potent activator of TGASE: The activation of TGase results in increased transamidation of RhoA, which is inhibited by monodansylcadaverine (MDC; an inhibitor of transglutaminase activity) and TGaseM (a TGase mutant lacking transglutaminase activity). Transamidated RhoA functions as a constitutively active G-protein, showing increased binding to its downstream target, RhoA-associated kinase-2 (ROCK-2). Upon binding to RhoA, ROCK-2 becomes autophosphorylated and demonstrates stimulated kinase activity. The RA-stimulated interaction between RhoA and ROCK-2 is blocked by MDC and TGaseM, indicating a role for transglutaminase activity in the interaction. Biochemical effects of TGase activation, coupled with the formation of stress fibers and focal adhesion complexes, are proposed to have a significant role in cell differentiation.
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Transglutamination of the Gln63 residue abolishes the intrinsic and GAP-stimulated GTPase activity of RhoA, leading to its permanent activation.
“Finally, various types of transglutamination of the Gln63 residue have been found to abolish the intrinsic and GAP-stimulated GTPase activity of RhoA, leading to its permanent activation [74,75,76].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [75]
The Discussion identifies Gln63 as a critical site for RhoA transamidation, and the paper describes transamidated RhoA as constitutively active. However, the Introduction attributes abolition of intrinsic and GAP-stimulated GTP hydrolysis specifically to deamidation of Gln63, not transamidation. The claimed mechanism for transamidation is therefore not established by this paper. (LLM, conf=0.88)
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Cites
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Bourne, H. R., Sanders, D. A., & McCormick, F. (1991) · Nature · doi:10.1038/349117a0 · Cited by 3,392 · see citing works
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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
- Singh, U. S., Kunar, M. T., Kao, Y., & Baker, K. M.
- Affiliations
- Texas A&M Health Science Center (US)
- Corresponding author
- Singh, Ugra S.
- Venue
- The EMBO Journal
- Published
- 2001-05-15
- Volume
- 20
- Issue
- 10
- Pages
- 2413-2423
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC125450
- OpenAlex
- W2039339016
- Cited by
- 88
- References
- 1
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 5
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- U.S. Public Health Service (58439)
- National Heart, Lung, and Blood Institute (HL-60529, R01HL060529)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- retinoic acid, RhoA, transamidation, post-translational modification, monodansylcadaverine, autophosphorylation, G protein signaling, stress fibers, focal adhesions, cell differentiation
- MeSH terms
- Protein Glutamine gamma Glutamyltransferase 2, Cytoskeleton, Enzyme Activation, HeLa Cells, Humans, Transglutaminases, Tretinoin, Protein Serine-Threonine Kinases, GTP-Binding Proteins, rhoA GTP-Binding Protein, Focal Adhesions, Intracellular Signaling Peptides and Proteins, rho-Associated Kinases
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