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

Bruurs, Lucas J.M.; Donker, Lisa; Zwakenberg, Susan; Zwartkruis, Fried; Begthel, Harry; Knisely, Alexander S.; Posthuma, George; Graaf, Stan F.J. van de; Paulusma, Coen C.; Bos, Johannes L.

doi:10.1083/jcb.201505118

Cited by 19 publications

(28 citation statements)

References 30 publications

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“…Indeed, proper activation and recruitment of Cdc42 to the plasma membrane requires the oscillation of local PS concentration, which can be regulated by PE-flippase activity; that is, an increase in PE-flipping activity decreases the local PS concentration on the plasma membrane (Das et al, 2012;Saito et al, 2007). Similarly, ATP8B1 is required for the polarized localization of Cdc42 in mammalian cells (Bruurs et al, 2015). Because ATP8B1 is a PC flippase (Takatsu et al, 2014), the oscillation of local PS concentration can be regulated by PC-flippase activity of ATP8B1 to allow the proper activation and local clustering of Cdc42 at the apical membranes (Bruurs et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The cytoplasmic C-terminal region of the ATP11C variant determines its localization at the polarized plasma membrane

Takayama

Takatsu

Hamamoto

et al. 2019

Journal of Cell Science

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ATP11C, a member of the P4-ATPase family, is a major phosphatidylserine (PS)-flippase located at the plasma membrane. ATP11C deficiency causes a defect in B-cell maturation, anemia and hyperbilirubinemia. Although there are several alternatively spliced variants derived from the ATP11C gene, the functional differences between them have not been considered. Here, we compared and characterized three C-terminal spliced forms (we designated as ATP11C-a, ATP11C-b and ATP11C-c), with respect to their expression patterns in cell types and tissues, and their subcellular localizations. We had previously shown that the C-terminus of ATP11C-a is critical for endocytosis upon PKC activation. Here, we found that ATP11C-b and ATP11C-c did not undergo endocytosis upon PKC activation. Importantly, we also found that ATP11C-b localized to a limited region of the plasma membrane in polarized cells, whereas ATP11C-a was distributed on the entire plasma membrane in both polarized and non-polarized cells. Moreover, we successfully identified LLXY residues within the ATP11C-b C-terminus as a critical motif for the polarized localization. These results suggest that the ATP11C-b regulates PS distribution in distinct regions of the plasma membrane in polarized cells.

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Section: Discussionmentioning

confidence: 99%

The cytoplasmic C-terminal region of the ATP11C variant determines its localization at the polarized plasma membrane

Takayama

Takatsu

Hamamoto

et al. 2019

Journal of Cell Science

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“…We previously reported that these Cdc42 knockout cells retain the ability to form a brush border but are nonetheless unable to ensure that polarization is restricted to a single site (3). We find that the singularity defect in the W4:NEC cells is rescued by reintroduction of wild-type Cdc42, demonstrating that yellow fluorescent protein (YFP)-tagged Cdc42 is still functional (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Two-Tiered Mechanism Enables Localized Cdc42 Signaling during Enterocyte Polarization

Bruurs

Zwakenberg

Net

et al. 2017

Molecular and Cellular Biology

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Signaling by the small GTPase Cdc42 governs a diverse set of cellular processes that contribute to tissue morphogenesis. Since these processes often require highly localized signaling, Cdc42 activity must be clustered in order to prevent ectopic signaling. During cell polarization, apical Cdc42 signaling directs the positioning of the nascent apical membrane. However, the molecular mechanisms that drive Cdc42 clustering during polarity establishment are largely unknown. Here, we demonstrate that during cell polarization localized Cdc42 signaling is enabled via activity-dependent control of Cdc42 mobility. By performing photoconversion experiments, we show that inactive Cdc42-GDP is 30-fold more mobile than active Cdc42-GTP. This switch in apical mobility originates from a dual mechanism involving RhoGDI-mediated membrane dissociation of Cdc42-GDP and Tuba-mediated immobilization of Cdc42-GTP. Interference with either mechanism affects Cdc42 clustering and as a consequence impairs Cdc42-mediated apical membrane clustering. We therefore identify a molecular network, comprised of Cdc42, the guanine nucleotide exchange factor (GEF) Tuba, and RhoGDI, that enables differential diffusion of inactive and active Cdc42 and is required to establish localized Cdc42 signaling during enterocyte polarization.

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“…Subsequently, a nonsense mutation in the Atp11c gene was identified in UPS-1 cells (70). Several lines of evidence suggest that ATP8B1 translocates PS in bile canaliculi and apical membranes (72,74,75). In another study, RNA interference-mediated depletion of ATP8B1 did not affect translocation of PS in Caco-2 cells (76).…”

Section: Lipid Transport By P4-atpasesmentioning

confidence: 99%

Substrates of P4‐ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine)

Shin

Takatsu

2018

FASEB j.

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P4‐ATPases, a subfamily of P‐type ATPases, were initially identified as aminophospholipid translocases in eukaryotic membranes. These proteins generate and maintain membrane lipid asymmetry by translocating aminophospholipids (phosphatidylserine and phosphatidylethanolamine) from the exoplasmic/lumenal leaflet to the cytoplasmic leaflet. The human genome encodes 14 P4‐ATPases, and the cellular localizations, substrate specificities, and cellular roles of these proteins were recently revealed. Numerous P4‐ATPases, including ATP8A1, ATP8A2, ATP11A, ATP11B, and ATP11C, transport phosphatidylserine. By contrast, ATP8B1, ATP8B2, and ATP10A transport phosphatidylcholine but not aminophospholipids, although there is a discrepancy regarding the substrate of ATP8B1 in the literature. Some yeast and plant P4‐ATPases can also translocate phosphatidylcholine. At least 2 P4‐ATPases (ATP8A2 and ATP8B1) are associated with severe human diseases, and other P4‐ATPases are implicated in various pathophysiologic conditions in mouse models. Here, we discuss the cellular functions of phosphatidylcholine flippases and suggest a model for the phenotype of progressive familial intrahepatic cholestasis 1 caused by a defect in ATP8B1.—Shin, H.‐W., Takatsu, H. Substrates of P4‐ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine). FASEB J. 33, 3087–3096 (2019). http://www.fasebj.org

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

Abstract: The disease-associated phospholipid flippase ATP8B1 decreases Cdc42 mobility at the apical membrane to ensure the formation of a single apical domain and to maintain healthy lumen architecture.

Cited by 19 publications

References 30 publications

The cytoplasmic C-terminal region of the ATP11C variant determines its localization at the polarized plasma membrane

The cytoplasmic C-terminal region of the ATP11C variant determines its localization at the polarized plasma membrane

A Two-Tiered Mechanism Enables Localized Cdc42 Signaling during Enterocyte Polarization

Substrates of P4‐ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine)

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