Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes
Open accessAbstract
We have observed that stimulation of human natural killer cells with dibutyryl cAMP (Bt2cAMP) reproduced the effects of ADP ribosylation of the GTP binding protein RhoA by Clostridium botulinum C3 transferase: both agents induced similar morphological changes, inhibited cell motility and blocked the cytolytic function. We demonstrate here that cAMP-dependent protein kinase A (PKA) phosphorylates RhoA in its C-terminal region, on serine residue 188. This phosphorylation does not affect the ability of recombinant RhoA to bind guanine nucleotides, nor does it modify its intrinsic GTPase activity. However, treatment of cells with Bt2cAMP results in the translocation of membrane-associated RhoA towards the cytosol. Experiments using purified membrane preparations indicated that Rho-GDP dissociation inhibitor, which can complex phosphorylated RhoA in its GTP-bound state, was the effector of this translocation. Taken together, these data suggest that PKA phosphorylation of RhoA is a central event in mediating the cellular effects of cAMP, and support the existence of an alternative pathway for terminating RhoA signalling whereby GTP-bound RhoA, when phosphorylated, could be separated from its putative effector(s) independently of its GTP/GDP cycling.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PKA/PKG-mediated phosphorylation of RhoA on Ser188 inhibits RhoA activity by favoring interaction with RhoGDI, leading to extraction from the plasma membrane, and protects GTP-bound RhoA from ubiquitin-mediated proteasomal degradation.
“The most well-studied phosphorylation event of RhoA is protein kinase A (PKA) and cyclic GMP-dependent protein kinase (PKG)-mediated phosphorylation on Ser188, close to the prenylated Cys190 in the C-terminus [49,50,56]. This phosphorylation inhibits RhoA activity by favoring interaction with RhoGDI, leading to its extraction from the plasma membrane [50,51,55], and protects GTP-bound RhoA from ub”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [49]
The Results passages show that PKA phosphorylates RhoA at Ser188, increases RhoGDI binding to phosphorylated RhoA-GTP, and enables GDI to extract RhoA from membranes. The Discussion says this may terminate RhoA signalling, but explicitly states that the fate of phosphorylated RhoA-GTP was not investigated. Our copy does not establish PKG-mediated phosphorylation or protection from ubiquitin-mediated proteasomal degradation. Page numbers are unavailable in the indexed passages. (LLM, conf=0.89)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Smeal, T., Binetruy, B., Mercola, D. A., Birrer, M., & Karin, M. (1991) · Nature · doi:10.1038/354494a0 · Cited by 789 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Kamiguian,A., Zaharoui,A. and Tavitian,A. (1993) Identification of small GTP-binding rab proteins in human platelets: thrombin induced phosphorylation of rab3b, rab6 and rab8 proteins. Proc. Natl Acad. Sci. USA, 90, 7647-7651.
- Lapetina,E.G., Lacal,J.C., Reep,B.R. and Molina y Vedia,L. (1989) A ras-related protein is phosphorylated and translocated by agonists that increase cAMP levels in human platelets. Proc. Natl Acad. Sci. USA, 86, 3131-3134.
- Springer.T.A. (1989) Adhesion receptors of the immune system. Naitur-e. 346. 425-434.
Cited by
Sorted by citations
Ras history: The saga continues
Cox, A. D., & Der, C. J. (2010) · Small GTPases · doi:10.4161/sgtp.1.1.12178 · Cited by 706 · see citing works
Targeting protein prenylation for cancer therapy
Berndt, N., Hamilton, A. D., & Sebti, S. M. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3151 · Cited by 614 · see citing works
Mitchell, S., Thomas, G., Harvey, K., Cottell, D., Reville, K., Berlasconi, G., Petasis, N. A., Erwig, L., Rees, A. J., Savill, J., et al. (2002) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000032417.73640.72 · Cited by 287 · see citing works
Lingor, P., Teusch, N., Schwarz, K., Mueller, R., Mack, H., Bähr, M., & Mueller, B. K. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04756.x · Cited by 214 · see citing works
Huang, L., Szymanska, K., Jensen, V. L., Janecke, A. R., Innes, A. M., Davis, E. E., Frosk, P., Li, C., Willer, J. R., Chodirker, B. N., et al. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.11.005 · Cited by 194 · see citing works
Transforming growth factor-β1 regulates macrophage migration via RhoA
Kim, J.-S., Kim, J.-G., Moon, M.-Y., Jeon, C.-Y., Won, H.-Y., Kim, H.-J., Jeon, Y.-J., Seo, J.-Y., Kim, J.-I., Kim, J., et al. (2006) · Blood · doi:10.1182/blood-2005-10-009191 · Cited by 134 · 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
Leung, C., & Wong, Y. (2017) · Molecules · doi:10.3390/molecules22071239 · Cited by 48 · see citing works
Role of PKA as a negative regulator of PCP signaling pathway during Xenopus gastrulation movements
Park, E., Kim, G.-H., Choi, S.-C., & Han, J.-K. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.01.011 · Cited by 41 · see citing works
- Authors
- Lang, P., Gesbert, F., Delespine‐Carmagnat, M., Stancou, R., Pouchelet, M., & Bertoglio, J.
- Affiliations
- Inserm (FR)
- Venue
- The EMBO Journal
- Published
- 1996-02-01
- Volume
- 15
- Issue
- 3
- Pages
- 510-519
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC449969
- OpenAlex
- W1236053900
- Cited by
- 558
- References
- 1
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 4 · 2022: 12 · 2021: 10 · 2020: 8 · 2019: 13 · 2018: 6 · 2017: 17 · 2016: 17 · 2015: 13 · 2014: 19 · 2013: 17 · 2012: 25
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- RhoA, protein kinase A, cAMP signaling, natural killer cells, cytotoxic lymphocytes, Rho GDP dissociation inhibitor, cell motility, cytotoxicity, ADP-ribosylation, GTPase activity
- MeSH terms
- Cyclic AMP, Amino Acid Sequence, Binding Sites, Biological Transport, Active, Botulinum Toxins, Cell Line, Cytosol, Bucladesine, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Killer Cells, Natural, Molecular Sequence Data, Phosphorylation, Recombinant Fusion Proteins, Cyclic AMP-Dependent Protein Kinases, GTP-Binding Proteins, rhoA GTP-Binding Protein, ADP Ribose Transferases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
