Establishing epithelial glandular polarity: interlinked roles for ARF6, Rac1, and the matrix microenvironment

Monteleon, Christine L.; Sedgwick, Alanna; Hartsell, Alyssa; Dai, Michael S.; Whittington, Catherine F.; Voytik‐Harbin, Sherry L.; D’Souza‐Schorey, Crislyn

doi:10.1091/mbc.e12-03-0246

Cited by 22 publications

(25 citation statements)

References 34 publications

(53 reference statements)

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“…1). The percentage of cysts with inverted polarity observed in our study is also consistent to the outcomes (30-50%) recently published in different studies 34-40 . Moreover in the p110δ depleted and inverted polarized cysts, no laminin (Fig.…”

Section: Resultssupporting

confidence: 93%

“…The laminins are major and important biologically active components of the basement membrane (BM), a thin layer of ECM underlying epithelial cells. Several publications have now reported the crucial role of laminins in orientation of apico-basal polarity axis through the activation of Rac1 31-32-33-34 . PI3Ks are important regulators of Rac1 21-35 and its implication in Rac1-mediated regulation of lumen formation has been evoked 36 .…”

Section: Resultsmentioning

confidence: 99%

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Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

et al. 2015

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Signaling triggered by adhesion to the extracellular matrix plays a key role in the spatial orientation of epithelial polarity and formation of lumens in glandular tissues. Phosphoinositide 3-kinase signaling in particular is known to influence the polarization process during epithelial cell morphogenesis. Here, using Madin-Darby canine kidney epithelial cells grown in 3D culture, we show that the p110δ isoform of phosphoinositide 3-kinase colocalizes with focal adhesion proteins at the basal surface of polarized cells. Pharmacological, siRNA- or kinase-dead mediated inhibition of p110δ impair the early stages of lumen formation, resulting in inverted polarized cysts, with no laminin or type IV collagen assembly at cell/extracellular matrix contacts. p110δ also regulates the organization of focal adhesions and membrane localization of dystroglycan. Thus, we uncover a previously unrecognized role for p110δ in epithelial cells in the orientation of the apico-basal axis and lumen formation.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

et al. 2015

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“…Madin-Darby canine kidney (MDCK) cells with tetracycline-regulated expression of HA-tagged ARF6 mutants, MDCK ARF6(Q67L) and MDCK ARF6(T27N) , were grown as described previously (40). MDCK ARF6si cells, with inducible expression of ARF6 small interfering RNA (siRNA), were grown as described previously (41). Parental L cells and L cells expressing Wnt3A (L-Wnt3A) were obtained from the American Type Culture Collection (ATCC).…”

Section: Methodsmentioning

confidence: 99%

ARF6-Regulated Endocytosis of Growth Factor Receptors Links Cadherin-Based Adhesion to Canonical Wnt Signaling in Epithelia

Pellón-Cárdenas

Clancy

Uwimpuhwe

et al. 2013

Molecular and Cellular Biology

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Wnt signaling has an essential role in embryonic development as well as stem/progenitor cell renewal, and its aberrant activation is implicated in many diseases, including several cancers. ␤-Catenin is a critical component of Wnt-mediated transcriptional activation. Here we show that ARF6 activation during canonical Wnt signaling promotes the intracellular accumulation of ␤-catenin via a mechanism that involves the endocytosis of growth factor receptors and robust activation of extracellular signalregulated kinase (ERK). ERK promotes casein kinase 2-mediated phosphorylation of ␣-catenin, leading to destabilization of the adherens junctions and a subsequent increase in cytoplasmic pools of active ␤-catenin and E-cadherin. ERK also phosphorylates LRP6 to amplify the Wnt transduction pathway. The aforementioned Wnt-ERK signaling pathway initiates lumen filling of epithelial cysts by promoting cell proliferation in three-dimensional cell cultures. This study elucidates a mechanism responsible for the switch in ␤-catenin functions in cell adhesion at the adherens junctions and Wnt-induced nuclear signaling.

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“…30,41 These observations suggest that blocking of vesicle tethering to the AMIS is unlikely to be the sole reason for polarity inversion and an additional mechanism should be involved in Rab35-dependent polarity establishment. Because polarity inversion has previously been observed in cysts with perturbed pathways connected with Arf6 and b1-integrin signaling 5,44,45 and because Rab35 has already been shown to regulate b1-integrin trafficking, 46 it is possible that a defect in Rab35-dependent b1-integrin recycling is partially responsible for polarity inversion in Rab35-KD (or Rab35-knockout) cysts. It should be noted that this phenotype was mimicked by depletion of another Rab35 effector ACAP2, but not by OCRL that functions in PCX trafficking in 2D cell culture.…”

Section: 41mentioning

confidence: 99%

Regulation of podocalyxin trafficking by Rab small GTPases in epithelial cells

Mrozowska

Fukuda

2016

Small GTPases

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The characteristic feature of polarity establishment in MDCK II cells is transcytosis of apical glycoprotein podocalyxin (PCX) from the outer plasma membrane to the newly formed apical domain. This transcytotic event consists of multiple steps, including internalization from the plasma membrane, transport through early endosomes and Rab11-positive recycling endosomes, and delivery to the apical membrane. These steps are known to be tightly coordinated by Rab small GTPases, which act as molecular switches cycling between active GTP-bound and inactive GDPbound states. However, our knowledge regarding which sets of Rabs regulate particular steps of PCX trafficking was rather limited. Recently, we have performed a comprehensive analysis of Rab GTPase engagement in the transcytotic pathway of PCX during polarity establishment in 2-dimensional (2D) and 3-dimensional (3D) MDCK II cell cultures. In this Commentary we summarize our findings and set them in the context of previous reports.

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Establishing epithelial glandular polarity: interlinked roles for ARF6, Rac1, and the matrix microenvironment

Cited by 22 publications

References 34 publications

Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

Phosphoinositide 3-kinase p110δ promotes lumen formation through the enhancement of apico-basal polarity and basal membrane organization

ARF6-Regulated Endocytosis of Growth Factor Receptors Links Cadherin-Based Adhesion to Canonical Wnt Signaling in Epithelia

Regulation of podocalyxin trafficking by Rab small GTPases in epithelial cells

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