ATP8B1-mediated spatial organization of Cdc42 signaling maintains singularity during enterocyte polarization

During yeast cell polarization localization of the small GTPase, cell division control protein 42 homologue (Cdc42) is clustered to ensure the formation of a single bud. Here we show that the disease-associated flippase ATPase class I type 8b member 1 (ATP8B1) enables Cdc42 clustering during enteroc...

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Bibliographic Details
Published in:The Journal of cell biology 2015-09, Vol.210 (7), p.1055-1063
Main Authors: Bruurs, Lucas J M, Donker, Lisa, Zwakenberg, Susan, Zwartkruis, Fried J, Begthel, Harry, Knisely, A S, Posthuma, George, van de Graaf, Stan F J, Paulusma, Coen C, Bos, Johannes L
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Adenosine Triphosphatases - metabolism
Animals
cdc42 GTP-Binding Protein - genetics
cdc42 GTP-Binding Protein - metabolism
Cell division
Cell Line
Cell Polarity - physiology
Cellular biology
Enterocytes - cytology
Enterocytes - metabolism
Humans
Lipids
Membrane Lipids - genetics
Membrane Lipids - metabolism
Membranes
Mice
Phospholipid Transfer Proteins - genetics
Phospholipid Transfer Proteins - metabolism
Proteins
Signal Transduction - physiology
Yeast
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Summary:During yeast cell polarization localization of the small GTPase, cell division control protein 42 homologue (Cdc42) is clustered to ensure the formation of a single bud. Here we show that the disease-associated flippase ATPase class I type 8b member 1 (ATP8B1) enables Cdc42 clustering during enterocyte polarization. Loss of this regulation results in increased apical membrane size with scattered apical recycling endosomes and permits the formation of more than one apical domain, resembling the singularity defect observed in yeast. Mechanistically, we show that to become apically clustered, Cdc42 requires the interaction between its polybasic region and negatively charged membrane lipids provided by ATP8B1. Disturbing this interaction, either by ATP8B1 depletion or by introduction of a Cdc42 mutant defective in lipid binding, increases Cdc42 mobility and results in apical membrane enlargement. Re-establishing Cdc42 clustering, by tethering it to the apical membrane or lowering its diffusion, restores normal apical membrane size in ATP8B1-depleted cells. We therefore conclude that singularity regulation by Cdc42 is conserved between yeast and human and that this regulation is required to maintain healthy tissue architecture.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201505118