Modulation of Rho Guanine Exchange Factor Lfc Activity by Protein Kinase A-Mediated Phosphorylation
Open accessAbstract
Lfc is a guanine nucleotide exchange factor (GEF) for Rho that demonstrates an unusual ability to associate with microtubules. While several phosphorylated residues have been detected in the Lfc polypeptide, the mechanism(s) by which phosphorylation regulates the exchange activity of Lfc remains unclear. We confirm that Lfc is a phosphorylated protein and demonstrate that 14-3-3 interacts directly and in a phosphorylation-dependent manner with Lfc. We identify AKAP121 as an Lfc-binding protein and show that Lfc is phosphorylated in an AKAP-dependent manner by protein kinase A (PKA). Forskolin treatment induced 14-3-3 binding to Lfc and suppressed the exchange activity of wild-type Lfc on RhoA. Importantly, a mutant of Lfc that is unable to associate with 14-3-3 proteins was resistant to inhibition by forskolin. Tctex-1, a dynein motor light chain, binds to Lfc in a competitive manner with 14-3-3.
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GEF-H1 is required for LPA/thrombin-induced stress fibre formation and focal adhesion formation following stimulation with tumour necrosis factor-a, LPA or thrombin.
“GEF-H1 is required for LPA/thrombin-induced stress fibre formation, and focal adhesion formation following stimulation with tumour necrosis factor-a, LPA or thrombin 2,3,6 .”
From Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1 (2014) · cites this paper as [3]
The Introduction identifies Lfc as GEF-H1 and says its depletion impairs actin reorganization after LPA or thrombin; the Results directly show that Lfc depletion prevents LPA-induced stress fibres. The Results also say Lfc modulates focal-adhesion assembly downstream of LPA, but the passages do not support the claim about focal-adhesion formation after tumour necrosis factor-α or thrombin stimulation. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPKA phosphorylates and inhibits GEF-H1 by creating a 14-3-3-binding site.
“In a previous publication, we found that PKA phosphorylates and inhibits GEF-H1 by creating a 14-3-3-binding site 3 , which strongly suggests that a cellular phosphatase(s) is involved in the activation of GEF-H1.”
From Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1 (2014) · cites this paper as [3]
Phosphorylation of GEF-H1 Ser885 by PKA creates a high-affinity 14-3-3-binding site that inhibits GEF-H1 exchange activity.
“Phosphorylation of Ser885 creates a high-affinity 14-3-3-binding site that inhibits the exchange activity of GEF-H1 (ref.3).”
From Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1 (2014) · cites this paper as [3]
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Cites
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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Research works printed but not linked: 4
- [5]5. Bakal, C. J., D. Finan, J. LaRose, C. D. Wells, G. Gish, S. Kulkarni, P. DeSepulveda, A. Wilde, and R. Rottapel. 2005. The Rho GTP exchange factor Lfc promotes spindle assembly in early mitosis. Proc. Natl. Acad. Sci. USA 102: 9529-9534.
- [16]16. Debant, A., C. Serra-Pages, K. Seipel, S. O'Brien, M. Tang, S. H. Park, and M. Streuli. 1996. The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains. Proc. Natl. Acad. Sci. USA 93: 5466-5471.
- [27]27. Gauthier-Fisher, A., D. C. Lin, M. Greeve, D. R. Kaplan, R. Rottapel, and F. D. Miller. 17 May 2009, posting date. Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells. Nat. Neurosci. doi:10.1038/nn.2339. · DOI
- [50]50. Suzuki, N., S. Nakamura, H. Mano, and T. Kozasa. 2003. G 𝛂 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc. Natl. Acad. Sci. USA 100: 733-738.
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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
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- Authors
- Meiri, D., Greeve, M. A., Brunet, A., Finan, D., Wells, C. D., LaRose, J., & Rottapel, R.
- Affiliations
- MaRS (CA)
- Ontario Cancer Institute, Toronto Medical Discovery Tower, 101 College St., Toronto, Ontario M5G 1L7, Canada
- Mount Sinai Hospital (CA)
- Corresponding author
- Rottapel, Robert
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2009-11-01
- Volume
- 29
- Issue
- 21
- Pages
- 5963-5973
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2772734
- OpenAlex
- W2127289971
- Cited by
- 71
- References
- 1
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 7 · 2016: 4 · 2015: 5 · 2014: 3 · 2013: 10 · 2012: 6
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Colorado State University
- University of Toronto
- University of North Carolina at Chapel Hill
- National Cancer Institute
- 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 › 14-3-3 protein interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- RhoA, protein kinase A, phosphorylation, 14-3-3 proteins, microtubule association, Tctex-1, forskolin
- MeSH terms
- Animals, Cell Line, Dyneins, Enzyme Activation, Humans, Microtubule-Associated Proteins, Nuclear Proteins, Phosphoproteins, Phosphorylation, Protein Binding, Consensus Sequence, Cyclic AMP-Dependent Protein Kinases, Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, Stress Fibers, GTP-Binding Protein alpha Subunits, G12-G13, 14-3-3 Proteins, Mice, Rats, A Kinase Anchor Proteins, t-Complex Genome Region, Rho Guanine Nucleotide Exchange Factors
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