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Cited by 149Protein Kinase Regulation and GTPase SignalingCellular Mechanics and InteractionsCellular transport and secretion

Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells

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Tkachenko, Eugene, Sabouri-Ghomi, Mohsen, Pertz, Olivier, Kim, Chungho, Gutierrez, Edgar, Machacek, Matthias, Groisman, Alex, Danuser, Gaudenz +1 more·2011·Nature Cell Biology
DOI 10.1038/ncb2231PMC PMC3746034
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Abstract

The cyclical protrusion and retraction of the leading edge is a hallmark of many migrating cells involved in processes such as development, inflammation and tumorigenesis. The molecular identity of the signalling mechanisms that control these cycles has remained unknown. Here, we used live-cell imaging of biosensors to monitor spontaneous morphodynamic and signalling activities, and employed correlative image analysis to examine the role of cyclic-AMP-activated protein kinase A (PKA) in protrusion regulation. PKA activity at the leading edge is closely synchronized with rapid protrusion and with the activity of RhoA. Ensuing PKA phosphorylation of RhoA and the resulting increased interaction between RhoA and RhoGDI (Rho GDP-dissociation inhibitor) establish a negative feedback mechanism that controls the cycling of RhoA activity at the leading edge. Thus, cooperation between PKA, RhoA and RhoGDI forms a pacemaker that governs the morphodynamic behaviour of migrating cells.

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  • 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 [51]

    The Results section ('PKA Phosphorylation Regulates the Dynamics of RhoA Activation'; page unavailable) states that PKA phosphorylation of RhoA at Ser188 increases RhoGDI binding and reduces RhoA activity in part through sequestration from the membrane. The passages found do not establish PKG-mediated phosphorylation or protection of GTP-bound RhoA from ubiquitin-mediated proteasomal degradation. (LLM, conf=0.87)

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Research works printed but not linked: 52

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Authors
Tkachenko, E., Sabouri-Ghomi, M., Pertz, O., Kim, C., Gutierrez, E., Machacek, M., Groisman, A., Danuser, G., & Ginsberg, M. H.
Affiliations
  • University of California San Diego (US)
  • Scripps Research Institute (US)
  • University of Basel (CH)
Corresponding author
Ginsberg, Mark H.
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2011-05-15
Volume
13
Issue
6
Pages
660-667
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb2231
PMC
PMC3746034
OpenAlex
W2047026162
Cited by
149
References
0
Citations by year
2026: 4 · 2025: 2 · 2024: 3 · 2023: 6 · 2022: 12 · 2021: 6 · 2020: 11 · 2019: 12 · 2018: 5 · 2017: 9 · 2016: 10 · 2015: 14 · 2014: 12 · 2013: 21 · 2012: 16
FWCI
6.70
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (HL 31950, P01HL031950, F32HL094012)
  • National Institute of General Medical Sciences (GM071868, R01GM071868)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR027214, R37AR027214, AR 27214)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
protein kinase A, RhoA, RhoGDI, cell migration, leading edge protrusion, cell retraction, cardiac pacemaker, cAMP signaling, negative feedback
MeSH terms
Animals, Cell Line, Cell Movement, Dipodomys, Epithelial Cells, Female, Kidney, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Guanine Nucleotide Dissociation Inhibitors, rhoA GTP-Binding Protein, Rats, rho-Specific Guanine Nucleotide Dissociation Inhibitors

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