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Cited by 76Cellular transport and secretionProtein Kinase Regulation and GTPase SignalingExtracellular vesicles in disease

Exocyst function regulated by effector phosphorylation

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Chen, Xiao-Wei, Leto, Dara, Xiao, Junyu, Goss, John, Wang, Qian, Shavit, Jordan A., Xiong, Tingting, Yu, Genggeng +4 more·2011·Nature Cell Biology
DOI 10.1038/ncb2226PMC PMC3904505
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Abstract

The exocyst complex tethers vesicles at sites of fusion through interactions with small GTPases. The G protein RalA resides on Glut4 vesicles, and binds to the exocyst after activation by insulin, but must then disengage to ensure continuous exocytosis. Here we report that, after recognition of the exocyst by activated RalA, disengagement occurs through phosphorylation of its effector Sec5, rather than RalA inactivation. Sec5 undergoes phosphorylation in the G-protein binding domain, allosterically reducing RalA interaction. The phosphorylation event is catalysed by protein kinase C and is reversed by an exocyst-associated phosphatase. Introduction of Sec5 bearing mutations of the phosphorylation site to either alanine or aspartate disrupts insulin-stimulated Glut4 exocytosis, as well as other trafficking processes in polarized epithelial cells and during development of zebrafish embryos. The exocyst thus serves as a 'gatekeeper' for exocytic vesicles through a circuit of engagement, disengagement and re-engagement with G proteins.

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  • Ral is inactivated by PKC phosphorylation of the effector Sec5.

    “and it is inactivated by PKC phosphorylation of the effector Sec5 (Chen et al, 2011).”

    From Ral mediates activity‐dependent growth of postsynaptic membranes via recruitment of the exocyst (2013) · cites this paper as Chen et al, 2011

    The Introduction distinguishes RalA inactivation from modification of its exocyst partner Sec5 and reports that PKC phosphorylation causes Sec5 to dissociate from active RalA. The Results section on allosteric phosphorylation further shows that the released RalA can bind fresh, unphosphorylated Sec5. The paper therefore supports disruption of the RalA–Sec5 interaction, not inactivation of RalA. (LLM, conf=0.90)

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  • RalA regulates vesicle tethering and fusion through interacting with exocyst.

    “Ralbp1 binds to RalA, a small GTPase regulating vesicle tethering and fusion through interacting with exocyst (11, 20, 41–44).”

    From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [43]

  • Ralbp1 binds to RalA.

    “Ralbp1 binds to RalA, a small GTPase regulating vesicle tethering and fusion through interacting with exocyst (11, 20, 41–44).”

    From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [43]

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Research works printed but not linked: 42

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Authors
Chen, X.-W., Leto, D., Xiao, J., Goss, J., Wang, Q., Shavit, J. A., Xiong, T., Yu, G., Ginsburg, D., Toomre, D., Xu, Z., & Saltiel, A. R.
Affiliations
  • University of Michigan (US)
  • Yale University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Saltiel, Alan R.
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2011-04-24
Volume
13
Issue
5
Pages
580-588
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb2226
PMC
PMC3904505
OpenAlex
W2028302114
Cited by
76
References
0
Citations by year
2026: 1 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 8 · 2012: 13
FWCI
4.47
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
  • Howard Hughes Medical Institute
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (P60DK020572, R01DK061618, DK076906, R01DK076906)
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
exocyst complex, RalA, Sec5, vesicle tethering, exocytosis, GLUT4, insulin signaling, protein kinase C, phosphatase, small GTPases, allosteric regulation, polarized epithelial cells, zebrafish embryonic development, vesicle trafficking
MeSH terms
Allosteric Regulation, Animals, Exocytosis, Phosphorylation, Protein Kinase C, Zebrafish, GTP Phosphohydrolases, Biocatalysis

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