Phosphorylation by Protein Kinase Cα Regulates RalB Small GTPase Protein Activation, Subcellular Localization, and Effector Utilization
Open accessAbstract
Ras-like (Ral) small GTPases are regulated downstream of Ras and the noncanonical Ral guanine nucleotide exchange factor (RalGEF) effector pathway. Despite RalA and RalB sharing 82% sequence identity and utilization of shared effector proteins, their roles in normal and neoplastic cell growth have been shown to be highly distinct. Here, we determined that RalB function is regulated by protein kinase Cα (PKCα) phosphorylation. We found that RalB phosphorylation on Ser-198 in the C-terminal membrane targeting sequence resulted in enhanced RalB endomembrane accumulation and decreased RalB association with its effector, the exocyst component Sec5. Additionally, RalB phosphorylation regulated vesicular trafficking and membrane fusion by regulating v- and t-SNARE interactions. RalB phosphorylation regulated vesicular traffic of α5-integrin to the cell surface and cell attachment to fibronectin. In summary, our data suggest that phosphorylation by PKCα is critical for RalB-mediated vesicle trafficking and exocytosis.
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RalB undergoes regulatory phosphorylation at Ser198, promoting its re-localization to intracellular membranes and supporting functions in processes such as autophagy and vesicle trafficking.
“By contrast, RalB undergoes regulatory phosphorylation at Ser198, promoting its re-localization to intracellular membranes and supporting functions in processes such as autophagy and vesicle trafficking 42 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [42]
The Ser-198 phosphorylation section reports that Ser-198 regulates RalB movement from the plasma membrane to internal membranes. The Discussion links RalB phosphorylation to vesicle sorting and fusion. Although the introduction lists autophagy among processes regulated by Ral GTPases, the paper does not show that Ser-198 phosphorylation supports autophagy. Page numbers are unavailable in our copy. (LLM, conf=0.87)
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SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking
Lau, C. G., Takayasu, Y., Rodenas-Ruano, A., Paternain, A. V., Lerma, J., Bennett, M. V. L., & Zukin, R. S. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4933-08.2010 · Cited by 120 · see citing works
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- Morgan, A., Burgoyne, R. D., Barclay, J. W., Craig, T. J., Prescott, G. R., Ciufo, L. F., Evans, G. J., and Graham, M. E. (2005) Regulation of exocytosis by protein kinase C. Biochem. Soc. Trans. 33, 1341-1344
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Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
Self-citationDietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
Feng, X., Zhang, S., Wang, Y., Kurlagunda, T., Sit, A., Jaishankar, P., Yang, P., Sakane, S., Park, S. Y., Wisessaowapak, C., et al. (2026) · Nature · doi:10.1038/s41586-026-10697-z · Cited by 2 · see citing works
- Authors
- Martin, T. D., Mitin, N., Cox, A. D., Yeh, J. J., & Der, C. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Der, Channing J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 287
- Issue
- 18
- Pages
- 14827-14836
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3340265
- OpenAlex
- W2039195585
- Cited by
- 38
- References
- 1
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 4 · 2018: 1 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 3
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (5r01ca042978-30, CA042978, CA106991)
- National Cancer Institute (R01CA109550, R01-CA042978, R01CA140424, P50CA106991)
- National Institute of General Medical Sciences (T32GM007040)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- RalB, protein kinase C alpha, phosphorylation, small GTPases, Sec5, exocyst, vesicle trafficking, membrane fusion, SNARE proteins, integrin alpha5, subcellular localization, exocytosis
- MeSH terms
- Animals, Cell Line, Enzyme Activation, Exocytosis, Humans, Phosphorylation, ral GTP-Binding Proteins, Protein Transport, Vesicular Transport Proteins, SNARE Proteins, Rats, Protein Kinase C-alpha
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