Dynamic regulation of GEF-H1 localization at microtubules by Par1b/MARK2
Abstract
Par1b/MARK2 is a serine/threonine kinase that plays key roles in the development of cell polarity, but its precise mechanism of action remains unknown. Here we report that GEF-H1, a guanine nucleotide exchange factor for Rho-family small GTPases, is a novel substrate for Par1b. GEF-H1 directly associates with microtubules via its N-terminal C1 domain, which is known to regulate the activity of GEF-H1. Ectopically expressed GEF-H1 markedly promotes stabilization of microtubules, resulting in acetylation of microtubules. We find that Par1b phosphorylates GEF-H1 at three serine residues conserved in vertebrates and releases GEF-H1 from microtubules, which abrogates stabilization and acetylation of microtubules induced by GEF-H1 overexpression. The alanine mutant for the three phosphorylation sites (3SA) of GEF-H1 strongly induces stabilization and acetylation of microtubules, which was resistant to Par1b. Time-lapse imaging analyses reveal that GFP-fused GEF-H1 dynamically moved on microtubules from one protrusion to another, whereas the 3SA mutant was static. These data suggest that Par1b-phosphorylation regulates turnover of GEF-H1 localization by regulating its interaction with microtubules, which may contribute to cell polarization.
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Phosphorylation of GEFH1 by PAR-1/MARK at sites within the C1-DH linker near the C1 domain releases GEFH1 from microtubules.
“Phosphorylation of GEFH1 by partitioning-defective 1/microtubule affinity-regulating kinase (PAR-1/MARK) at sites within the C1-DH linker near the C1 domain releases GEFH1 from microtubules24”
From Structural basis of microtubule-mediated signal transduction (2026) · cites this paper as [24]
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LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR‐1
Lizcano, J. M., Göransson, O., Toth, R., Deak, M., Morrice, N. A., Boudeau, J., Hawley, S. A., Udd, L., Mäkelä, T. P., Hardie, D. G., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600110 · Cited by 1,381 · see citing works
Krendel, M., Zenke, F. T., & Bokoch, G. M. (2002) · Nature Cell Biology · doi:10.1038/ncb773 · Cited by 669 · see citing works
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Meiri, D., Marshall, C. B., Mokady, D., LaRose, J., Mullin, M., Gingras, A.-C., Ikura, M., & Rottapel, R. (2014) · Nature Communications · doi:10.1038/ncomms5857 · Cited by 70 · see citing works
Structural basis of microtubule-mediated signal transduction
Choi, S. R., Blum, T. B., Giono, M., Roy, B., Vakonakis, I., Schmid, D., Oelgarth, N., Ranganathan, A., Gossert, A. D., Shivashankar, G. V., et al. (2026) · Cell · doi:10.1016/j.cell.2025.11.011 · Cited by 14 · see citing works
OptoTAT reveals microtubule acetylation as a rapid trigger for GEF-H1–mediated cell migration
Deb Roy, A., Gonzalez, C. S., Stanislauskas, M., Shahid, F., Yadav, E., Rezek, J., & Inoue, T. (2026) · Journal of Cell Biology · doi:10.1083/jcb.202508095 · Cited by 2 · see citing works
- Authors
- Yoshimura, Y., & Miki, H.
- Affiliations
- Institute for Protein Research, The University of Osaka (JP)
- Corresponding author
- Miki, Hiroaki
- ORCID
- Miki, Hiroaki
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 408
- Issue
- 2
- Pages
- 322-328
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2067087164
- Cited by
- 39
- References
- 2
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 1 · 2020: 3 · 2019: 1 · 2017: 8 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 5 · 2012: 3
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- 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
- Keywords
- GEF-H1, MARK2, microtubule stabilization, microtubule acetylation, C1 domain, protein phosphorylation, Rho GTPases, cell polarity
- MeSH terms
- Acetylation, Amino Acid Sequence, Animals, Chlorocebus aethiops, Dogs, HeLa Cells, Humans, Microtubules, Molecular Sequence Data, Phosphorylation, Tubulin, Cell Polarity, Protein Serine-Threonine Kinases, COS Cells, Guanine Nucleotide Exchange Factors, Rho Guanine Nucleotide Exchange Factors
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