Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-018-19471-2
Title: Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination
Authors: Acosta, M.I
Urbach, S
Doye, A
Ng, Y.-W
Boudeau, J
Mettouchi, A
Debant, A
Manser, E 
Visvikis, O
Lemichez, E
Keywords: bacterial toxin
cytotoxic necrotizing factor 1
Escherichia coli protein
HACE1 protein, human
p21 activated kinase
Rac1 protein
RAC1 protein, human
serine
ubiquitin protein ligase
vasculotropin A
cell line
chemistry
human
metabolism
phosphorylation
protein multimerization
proteomics
ubiquitination
umbilical vein endothelial cell
Bacterial Toxins
Cell Line
Escherichia coli Proteins
Human Umbilical Vein Endothelial Cells
Humans
p21-Activated Kinases
Phosphorylation
Protein Multimerization
Proteomics
rac1 GTP-Binding Protein
Serine
Ubiquitin-Protein Ligases
Ubiquitination
Vascular Endothelial Growth Factor A
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Acosta, M.I, Urbach, S, Doye, A, Ng, Y.-W, Boudeau, J, Mettouchi, A, Debant, A, Manser, E, Visvikis, O, Lemichez, E (2018). Group-I PAKs-mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination. Scientific Reports 8 (1) : 1410. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-018-19471-2
Rights: Attribution 4.0 International
Abstract: The regulation of Rac1 by HACE1-mediated ubiquitination and proteasomal degradation is emerging as an essential element in the maintenance of cell homeostasis. However, how the E3 ubiquitin ligase activity of HACE1 is regulated remains undetermined. Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases downstream Rac1 activation by CNF1 toxin from pathogenic E. coli. Moreover, cell treatment with VEGF also promotes Ser-385 phosphorylation of HACE1. We have established in vitro that HACE1 is a direct target of PAK1 kinase activity. Mechanistically, we found that the phospho-mimetic mutant HACE1(S385E), as opposed to HACE1(S385A), displays a lower capacity to ubiquitinate Rac1 in cells. Concomitantly, phosphorylation of Ser-385 plays a pivotal role in controlling the oligomerization state of HACE1. Finally, Ser-385 phosphorylated form of HACE1 localizes in the cytosol away from its target Rac1. Together, our data point to a feedback inhibition of HACE1 ubiquitination activity on Rac1 by group-I PAK kinases. © 2018 The Author(s).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/178469
ISSN: 2045-2322
DOI: 10.1038/s41598-018-19471-2
Rights: Attribution 4.0 International
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