P114RhoGEF governs cell motility and lumen formation during tubulogenesis via ROCK-myosin II pathway

Kim, Minji; Shewan, Annette M.; Ewald, Andrew J.; Werb, Zena; Mostov, Keith E.

doi:10.1242/jcs.172361

Cited by 22 publications

(26 citation statements)

References 41 publications

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“…Both of these processes could also affect lumen continuity and/or tubule morphogenesis in vivo. Indeed, cell movements have been shown to resolve lumen discontinuities in in vitro epithelial tubes (Kim et al, 2015). Future studies, particularly those using live imaging, will be needed to elucidate the roles of these various processes in tubulogenesis.…”

Section: Discussionmentioning

confidence: 99%

Developing renal tubules orient cell division via Afadin to position the tubule lumen

et al. 2017

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In many types of tubules, continuity of the lumen is paramount to tubular function, yet how tubules generate lumen continuity is not known. We recently found that the F-actin-binding protein afadin is required for lumen continuity in developing renal tubules, though its mechanism of action remains unknown. Here, we demonstrate that afadin is required for lumen continuity by orienting the mitotic spindle during cell division. Using an 3D cyst model, we find that afadin localizes to the cell cortex adjacent to the spindle poles and orients the mitotic spindle. In tubules, cell division may be oriented relative to two axes: longitudinal and apical-basal. Unexpectedly, examination of early-stage developing nephron tubules reveals that cell division is not oriented in the longitudinal (or planar-polarized) axis. However, cell division is oriented perpendicular to the apical-basal axis. Absence of afadin leads to misorientation of apical-basal cell division in nephron tubules. Together, these results support a model whereby afadin determines lumen placement by directing apical-basal spindle orientation, resulting in a continuous lumen and normal tubule morphogenesis.

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Section: Discussionmentioning

confidence: 99%

Developing renal tubules orient cell division via Afadin to position the tubule lumen

et al. 2017

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“…Together, these analyses identified ARHGEF18 as the only RHOA-GEF exclusively activating the RHOA isoform (Blomquist et al, 2000;Herder et al, 2013), albeit biochemically it has also been described as a GEF for RAC1 (but not CDC42) (Niu et al, 2003). Arhgef18 activates RhoA at tight junctions, directly interacting with myosin IIA and regulating tight-junction assembly (Durgan et al, 2014;Kim et al, 2015;Terry et al, 2011;Xu et al, 2013). Thus, we interpret the similarity of defects in long-range communication induced by Arhgef18-and RhoA-depletion and direct inhibition of myosin-II contraction as indication that ARHGEF18 locates specifically at the top of an ARHGEF18/RHOA/MYO-II pathway (Fig.…”

Section: Actomyosin Contractility Disturbs Intercellular Communicatiomentioning

confidence: 97%

Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration

Zaritsky

Tseng

Rabadan

et al. 2016

Preprint

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Efficient collective migration depends on a balance between contractility and cytoskeletal rearrangements, adhesion, and mechanical cell-cell communication, all controlled by GTPases of the RHO family. By comprehensive screening of guanine nucleotide exchange factors (GEFs) in human bronchial epithelial cell monolayers, we identified GEFs that are required for collective migration at large, such as SOS1 and β-PIX, and RHOA GEFs that are implicated in intercellular communication. Downregulation of the latter GEFs differentially enhanced front-to-back propagation of guidance cues through the monolayer, and was mirrored by downregulation of RHOA expression and myosin-II activity. Phenotype-based clustering of knock-down behaviors identified RHOA-ARHGEF18 and ARHGEF3-ARHGEF28-ARHGEF11 clusters, indicating that the latter may signal through other RHO-family GTPases. Indeed, knock-down of RHOC produced an intermediate between the two phenotypes. We conclude that for effective collective migration the RHOA-GEFs-→ARHOA/C→ actomyosin pathways must be optimally tuned to compromise between generation of motility forces and restriction of intercellular communication.

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“…Interfering with the RhoA-ROCK-myosin-II contractility pathway has been shown to alter luminogenesis in MDCK cells (Ferrari et al, 2008;Kim et al, 2015;Rodríguez-Fraticelli et al, 2012). In particular, under permissive conditions, the constitutively active RhoAV14 mutant blocks the initial step of lumen formation (Ferrari et al, 2008).…”

Section: Efa6a and Actn1 Control Apical Contractility Contributing Tomentioning

confidence: 99%

EFA6 proteins regulate lumen formation through α-actinin 1

Milanini

Fayad

Partisani

et al. 2018

Journal of Cell Science

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A key step of epithelial morphogenesis is the creation of the lumen. Luminogenesis by hollowing proceeds through the fusion of apical vesicles at cell-cell contacts. The small nascent lumens grow through extension, coalescence and enlargement, coordinated with cell division, to give rise to a single central lumen. Here, by using MDCK cells grown in 3D-culture, we show that EFA6A (also known as PSD) participates in luminogenesis. EFA6A recruits α-actinin 1 (ACTN1) through direct binding. In polarized cells, ACTN1 was found to be enriched at the tight junction where it acts as a primary effector of EFA6A for normal luminogenesis. Both proteins are essential for the lumen extension and enlargement, where they mediate their effect by regulating the cortical acto-myosin contractility. Finally, ACTN1 was also found to act as an effector for the isoform EFA6B (also known as PSD4) in the human mammary tumoral MCF7 cell line. EFA6B restored the glandular morphology of this tumoral cell line in an ACTN1-dependent manner. Thus, we identified new regulators of cyst luminogenesis essential for the proper maturation of a newly-formed lumen into a single central lumen.

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P114RhoGEF governs cell motility and lumen formation during tubulogenesis via ROCK-myosin II pathway

Cited by 22 publications

References 41 publications

Developing renal tubules orient cell division via Afadin to position the tubule lumen

Developing renal tubules orient cell division via Afadin to position the tubule lumen

Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration

EFA6 proteins regulate lumen formation through α-actinin 1

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