Fat2 acts through the WAVE regulatory complex to drive collective cell migration during tissue rotation

Directional cell movements during morphogenesis require the coordinated interplay between membrane receptors and the actin cytoskeleton. The WAVE regulatory complex (WRC) is a conserved actin regulator. Here, we found that the atypical cadherin Fat2 recruits the WRC to basal membranes of tricellular contacts where a new type of planar-polarized whip-like actin protrusion is formed. Loss of either Fat2 function or its interaction with the WRC disrupts tricellular protrusions and results in the formation of nonpolarized filopodia. We provide further evidence for a molecular network in which the receptor tyrosine phosphatase Dlar interacts with the WRC to couple the extracellular matrix, the membrane, and the actin cytoskeleton during egg elongation. Our data uncover a mechanism by which polarity information can be transduced from a membrane receptor to a key actin regulator to control collective follicle cell migration during egg elongation. 4D-live imaging of rotating MCF10A mammary acini further suggests an evolutionary conserved mechanism driving rotational motions in epithelial morphogenesis.

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Rotating for elongation: Fat2 whips for the race

The Journal of Cell Biology ◽

10.1083/jcb.201601091 ◽

2016 ◽

Vol 212 (5) ◽

pp. 487-489 ◽

Cited By ~ 1

Author(s):

Tomke Stürner ◽

Gaia Tavosanis

Keyword(s):

Drosophila Melanogaster ◽

Cell Migration ◽

Actin Cytoskeleton ◽

Cell Shape ◽

Collective Cell Migration ◽

Cell Biol ◽

Regulatory Complex ◽

And Migration ◽

Cadherin Superfamily

Dynamic rearrangements of the actin cytoskeleton are crucial for cell shape and migration. In this issue, Squarr et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201508081) show that the cadherin superfamily protein Fat2 regulates actin-rich protrusions driving collective cell migration during Drosophila melanogaster egg morphogenesis through its interaction with the WAVE regulatory complex.

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Correction: Fat2 acts through the WAVE regulatory complex to drive collective cell migration during tissue rotation

The Journal of Cell Biology ◽

10.1083/jcb.20150808103082016c ◽

2016 ◽

Vol 212 (7) ◽

pp. 883-883 ◽

Cited By ~ 2

Author(s):

Anna Julia Squarr ◽

Klaus Brinkmann ◽

Baoyu Chen ◽

Tim Steinbacher ◽

Klaus Ebnet ◽

...

Keyword(s):

Cell Migration ◽

Collective Cell Migration ◽

Regulatory Complex

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Identification of the atypical cadherin FAT1 as a novel glypican-3 interacting protein in liver cancer cells

Scientific Reports ◽

10.1038/s41598-020-79524-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Panpan Meng ◽

Yi-Fan Zhang ◽

Wangli Zhang ◽

Xin Chen ◽

Tong Xu ◽

...

Keyword(s):

Cell Migration ◽

Cell Surface ◽

Transmembrane Protein ◽

Tyrosine Phosphatase ◽

Interacting Protein ◽

Extracellular Signaling ◽

Putative Receptor ◽

Elevated Expression ◽

A Cell ◽

Receptor Tyrosine Phosphatase

AbstractGlypican-3 (GPC3) is a cell surface heparan sulfate proteoglycan that is being evaluated as an emerging therapeutic target in hepatocellular carcinoma (HCC). GPC3 has been shown to interact with several extracellular signaling molecules, including Wnt, HGF, and Hedgehog. Here, we reported a cell surface transmembrane protein (FAT1) as a new GPC3 interacting protein. The GPC3 binding region on FAT1 was initially mapped to the C-terminal region (Q14517, residues 3662-4181), which covered a putative receptor tyrosine phosphatase (RTP)-like domain, a Laminin G-like domain, and five EGF-like domains. Fine mapping by ELISA and flow cytometry showed that the last four EGF-like domains (residues 4013-4181) contained a specific GPC3 binding site, whereas the RTP domain (residues 3662-3788) and the downstream Laminin G-2nd EGF-like region (residues 3829-4050) had non-specific GPC3 binding. In support of their interaction, GPC3 and FAT1 behaved concomitantly or at a similar pattern, e.g. having elevated expression in HCC cells, being up-regulated under hypoxia conditions, and being able to regulate the expression of EMT-related genes Snail, Vimentin, and E-Cadherin and promoting HCC cell migration. Taken together, our study provides the initial evidence for the novel mechanism of GPC3 and FAT1 in promoting HCC cell migration.

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Drosophila USP22/non-stop regulates the Hippo pathway to polarise the actin cytoskeleton during collective border cell migration

10.1101/2020.07.02.177170 ◽

2020 ◽

Author(s):

Hammed Badmos ◽

Neville Cobbe ◽

Amy Campbell ◽

Daimark Bennett

Keyword(s):

Cell Migration ◽

Actin Cytoskeleton ◽

Hippo Pathway ◽

Collective Cell Migration ◽

Deubiquitinating Enzymes ◽

Border Cell ◽

Border Cell Migration ◽

Actin Protrusions ◽

The Hippo Pathway

Polarisation of the actin cytoskeleton is vital for the collective migration of cells in vivo. During invasive border cell migration in Drosophila, actin polarisation is directly controlled by Hippo pathway components, which reside at contacts between border cells in the cluster. Here we identify, in a genetic screen for deubiquitinating enzymes involved in border cell migration, an essential role for non-stop/USP22 in the expression of Hippo pathway components expanded and merlin; loss of non-stop function consequently leads to a redistribution of F-actin and the polarity determinant Crumbs, loss of polarised actin protrusions and premature tumbling of the border cell cluster. Non-stop is a component of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional coactivator complex, but SAGA’s histone acetyltransferase module, which does not bind to expanded or merlin, is dispensable for migration. Taken together, our results uncover novel roles for SAGA-independent non-stop/USP22 in Hippo-mediated collective cell migration, which may help guide studies in other systems where USP22 is necessary for cell motility and invasion.

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Enhancement of endothelialization by topographical features is mediated by PTP1B-dependent endothelial adherens junctions remodeling

10.1101/766816 ◽

2019 ◽

Author(s):

Azita Gorji ◽

Pearlyn Jia Ying Toh ◽

Yi-Chin Toh ◽

Yusuke Toyama ◽

Pakorn Kanchanawong

Keyword(s):

Cell Migration ◽

Adherens Junctions ◽

Tyrosine Phosphatase ◽

Inhibitory Effect ◽

Cell Junctions ◽

Collective Cell Migration ◽

Combined Strategy ◽

Cell Migration And Proliferation ◽

Arterial Endothelial Cells ◽

Cell Cell

RationaleFailure of small synthetic vascular grafts is largely due to late endothelialization and has been an ongoing challenge in the treatment of cardiovascular diseases.ObjectivePrevious strategies developed to promote graft endothelialization include surface topographical modulation and biochemical modifications. However, these have been met with limited success. Importantly, although the integrity of Endothelial Cell (EC) monolayer is crucial for endothelialization, the crosstalk between surface topography and cell-cell connectivity is still not well understood. Here we explored a combined strategy that utilizes both topographical features and pharmacological perturbations.Methods and resultWe characterized EC behaviors in response to micron-scale grating topography in conjunction with pharmacological perturbations of endothelial adherens junctions (EAJ) regulators. We studied the EA.hy 926 cell-cell junctions and monolayer integrity using the junctional markers upon the inhibitory effect of EAJ regulator on both planar and grating topographies substrates.We identified a protein tyrosine phosphatase, PTP1B, as a potent regulator of EAJ stability. Next, we studied the physiologically relevant behaviors of EC using primary human coronary arterial endothelial cells (HCAEC). Our results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration to promote endothelialization.Our results showed that PTP1B inhibition synergized with grating topographies to modulate EAJ rearrangement, thereby controlling global EC monolayer sheet orientation, connectivity and collective cell migration and proliferation.ConclusionThe synergistic effect of PTP1B inhibition and grating topographies could be useful for the promotion of endothelialization by enhancing EC migration and proliferation.

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Drosophila USP22/nonstop polarizes the actin cytoskeleton during collective border cell migration

The Journal of Cell Biology ◽

10.1083/jcb.202007005 ◽

2021 ◽

Vol 220 (7) ◽

Author(s):

Hammed Badmos ◽

Neville Cobbe ◽

Amy Campbell ◽

Richard Jackson ◽

Daimark Bennett

Keyword(s):

Cell Migration ◽

Actin Cytoskeleton ◽

Hippo Pathway ◽

Collective Cell Migration ◽

Hippo Signaling ◽

Border Cell ◽

Signaling Complex ◽

Border Cell Migration ◽

Actin Protrusions

Polarization of the actin cytoskeleton is vital for the collective migration of cells in vivo. During invasive border cell migration in Drosophila, actin polarization is directly controlled by the Hippo signaling complex, which resides at contacts between border cells in the cluster. Here, we identify, in a genetic screen for deubiquitinating enzymes involved in border cell migration, an essential role for nonstop/USP22 in the expression of Hippo pathway components expanded and merlin. Loss of nonstop function consequently leads to a redistribution of F-actin and the polarity determinant Crumbs, loss of polarized actin protrusions, and tumbling of the border cell cluster. Nonstop is a component of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional coactivator complex, but SAGA’s histone acetyltransferase module, which does not bind to expanded or merlin, is dispensable for migration. Taken together, our results uncover novel roles for SAGA-independent nonstop/USP22 in collective cell migration, which may help guide studies in other systems where USP22 is necessary for cell motility and invasion.

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