scholarly journals Evi5 promotes collective cell migration through its Rab-GAP activity

2012 ◽  
Vol 198 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Carl Laflamme ◽  
Gloria Assaker ◽  
Damien Ramel ◽  
Jonas F. Dorn ◽  
Desmond She ◽  
...  
Keyword(s):  
Cell Migration ◽  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Gtpase Activating Proteins ◽  
Guidance Receptors ◽  
Dependent Polarization ◽  
Drosophila Protein ◽  
Molecular Machinery

Membrane trafficking has well-defined roles during cell migration. However, its regulation is poorly characterized. In this paper, we describe the first screen for putative Rab–GTPase-activating proteins (GAPs) during collective cell migration of Drosophila melanogaster border cells (BCs), identify the uncharacterized Drosophila protein Evi5 as an essential membrane trafficking regulator, and describe the molecular mechanism by which Evi5 regulates BC migration. Evi5 requires its Rab-GAP activity to fulfill its functions during migration and acts as a GAP protein for Rab11. Both loss and gain of Evi5 function blocked BC migration by disrupting the Rab11-dependent polarization of active guidance receptors. Altogether, our findings deepen our understanding of the molecular machinery regulating endocytosis and subsequently cell signaling during migration.

scholarly journals GAGA Regulates Border Cell Migration in Drosophila

2020 ◽  
Vol 21 (20) ◽  
pp. 7468
Author(s):  
Anna A. Ogienko ◽  
Lyubov A. Yarinich ◽  
Elena V. Fedorova ◽  
Natalya V. Dorogova ◽  
Sergey I. Bayborodin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Migration ◽  
Target Genes ◽  
Genetic Interaction ◽  
Follicle Cells ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Drosophila Oogenesis ◽  
Small Set ◽  
Multicellular Organisms

Collective cell migration is a complex process that happens during normal development of many multicellular organisms, as well as during oncological transformations. In Drosophila oogenesis, a small set of follicle cells originally located at the anterior tip of each egg chamber become motile and migrate as a cluster through nurse cells toward the oocyte. These specialized cells are referred to as border cells (BCs) and provide a simple and convenient model system to study collective cell migration. The process is known to be complexly regulated at different levels and the product of the slow border cells (slbo) gene, the C/EBP transcription factor, is one of the key elements in this process. However, little is known about the regulation of slbo expression. On the other hand, the ubiquitously expressed transcription factor GAGA, which is encoded by the Trithorax-like (Trl) gene was previously demonstrated to be important for Drosophila oogenesis. Here, we found that Trl mutations cause substantial defects in BC migration. Partially, these defects are explained by the reduced level of slbo expression in BCs. Additionally, a strong genetic interaction between Trl and slbo mutants, along with the presence of putative GAGA binding sites within the slbo promoter and enhancer, suggests the direct regulation of this gene by GAGA. This idea is supported by the reduction in the slbo-Gal4-driven GFP expression within BC clusters in Trl mutant background. However, the inability of slbo overexpression to compensate defects in BC migration caused by Trl mutations suggests that there are other GAGA target genes contributing to this process. Taken together, the results define GAGA as another important regulator of BC migration in Drosophila oogenesis.

scholarly journals Tousled-like kinase regulates cytokine-mediated communication between cooperating cell types during collective border cell migration

2016 ◽  
Vol 27 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Wenjuan Xiang ◽  
Dabing Zhang ◽  
Denise J. Montell
Keyword(s):  
Cell Migration ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Cell Types ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Stat Signaling ◽  
Border Cell Migration

Collective cell migration is emerging as a major contributor to normal development and disease. Collective movement of border cells in the Drosophila ovary requires cooperation between two distinct cell types: four to six migratory cells surrounding two immotile cells called polar cells. Polar cells secrete a cytokine, Unpaired (Upd), which activates JAK/STAT signaling in neighboring cells, stimulating their motility. Without Upd, migration fails, causing sterility. Ectopic Upd expression is sufficient to stimulate motility in otherwise immobile cells. Thus regulation of Upd is key. Here we report a limited RNAi screen for nuclear proteins required for border cell migration, which revealed that the gene encoding Tousled-like kinase (Tlk) is required in polar cells for Upd expression without affecting polar cell fate. In the absence of Tlk, fewer border cells are recruited and motility is impaired, similar to inhibition of JAK/STAT signaling. We further show that Tlk in polar cells is required for JAK/STAT activation in border cells. Genetic interactions further confirmed Tlk as a new regulator of Upd/JAK/STAT signaling. These findings shed light on the molecular mechanisms regulating the cooperation of motile and nonmotile cells during collective invasion, a phenomenon that may also drive metastatic cancer.

scholarly journals Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C

2010 ◽  
Vol 189 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Chieh Hsu ◽  
Yuichi Morohashi ◽  
Shin-ichiro Yoshimura ◽  
Natalia Manrique-Hoyos ◽  
SangYong Jung ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Rab Gtpase ◽  
Multivesicular Bodies ◽  
Dependent Manner ◽  
Intracellular Accumulation ◽  
Gtpase Activating Proteins ◽  
The Central Nervous System ◽  
And Function ◽  
Endosomal Vesicles ◽  
Activity Dependent

Oligodendrocytes secrete vesicles into the extracellular space, where they might play a role in neuron–glia communication. These exosomes are small vesicles with a diameter of 50–100 nm that are formed within multivesicular bodies and are released after fusion with the plasma membrane. The intracellular pathways that generate exosomes are poorly defined. Because Rab family guanosine triphosphatases (GTPases) together with their regulators are important membrane trafficking organizers, we investigated which Rab GTPase-activating proteins interfere with exosome release. We find that TBC1D10A–C regulate exosome secretion in a catalytic activity–dependent manner. We show that Rab35 is the target of TBC1D10A–C and that the inhibition of Rab35 function leads to intracellular accumulation of endosomal vesicles and impairs exosome secretion. Rab35 localizes to the surface of oligodendroglia in a GTP-dependent manner, where it increases the density of vesicles, suggesting a function in docking or tethering. These findings provide a basis for understanding the biogenesis and function of exosomes in the central nervous system.

scholarly journals A Drosophila RNAi screen reveals conserved glioblastoma-related adhesion genes that regulate collective cell migration

2021 ◽  
Author(s):  
Nirupama Kotian ◽  
Katie M Troike ◽  
Kristen N Curran ◽  
Justin D Lathia ◽  
Jocelyn A McDonald
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Invasion ◽  
Brain Parenchyma ◽  
Cell Junction ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Bioinformatics Analyses ◽  
Border Cell ◽  
Matrix Cell

Abstract Migrating cell collectives are key to embryonic development but also contribute to invasion and metastasis of a variety of cancers. Cell collectives can invade deep into tissues, leading to tumor progression and resistance to therapies. Collective cell invasion is also observed in the lethal brain tumor glioblastoma, which infiltrates the surrounding brain parenchyma leading to tumor growth and poor patient outcomes. Drosophila border cells, which migrate as a small cell cluster in the developing ovary, are a well-studied and genetically accessible model used to identify general mechanisms that control collective cell migration within native tissue environments. Most cell collectives remain cohesive through a variety of cell-cell adhesion proteins during their migration through tissues and organs. In this study, we first identified cell adhesion, cell matrix, cell junction, and associated regulatory genes that are expressed in human brain tumors. We performed RNAi knockdown of the Drosophila orthologs in border cells to evaluate if migration and/or cohesion of the cluster was impaired. From this screen, we identified eight adhesion-related genes that disrupted border cell collective migration upon RNAi knockdown. Bioinformatics analyses further demonstrated that subsets of the orthologous genes were elevated in the margin and invasive edge of human glioblastoma patient tumors. These data together show that conserved cell adhesion and adhesion regulatory proteins with potential roles in tumor invasion also modulate collective cell migration. This dual screening approach for adhesion genes linked to glioblastoma and border cell migration thus may reveal conserved mechanisms that drive collective tumor cell invasion.

scholarly journals Fascin limits Myosin activity within Drosophila border cells to control substrate stiffness and promote migration

2021 ◽  
Author(s):  
Maureen C. Lamb ◽  
Chathuri P. Kaluarachchi ◽  
Thiranjeewa I. Lansakara ◽  
Yiling Lan ◽  
Alexei V. Tivanski ◽  
...  
Keyword(s):  
Cell Migration ◽  
Nurse Cell ◽  
Cancer Metastasis ◽  
Critical Role ◽  
Substrate Stiffness ◽  
Cell Stiffness ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration

AbstractA key regulator of collective cell migrations, which drive development and cancer metastasis, is substrate stiffness. Increased substrate stiffness promotes migration and is controlled by Myosin. Using Drosophila border cell migration as a model of collective cell migration, we identify, for the first time, that the actin bundling protein Fascin limits Myosin activity in vivo. Loss of Fascin results in: increased activated Myosin on the border cells and their substrate, the nurse cells; decreased border cell Myosin dynamics; and increased nurse cell stiffness as measured by atomic force microscopy. Reducing Myosin restores on-time border cell migration in fascin mutant follicles. Further, Fascin’s actin bundling activity is required to limit Myosin activation. Surprisingly, we find that Fascin regulates Myosin activity in the border cells to control nurse cell stiffness to promote migration. Thus, these data shift the paradigm from a substrate stiffness-centric model of regulating migration, to uncover that collectively migrating cells play a critical role in controlling the mechanical properties of their substrate in order to promote their own migration. This new means of mechanical regulation of migration is likely conserved across contexts and organisms, as Fascin and Myosin are common regulators of cell migration.

scholarly journals Intracellular nanovesicles mediate integrin trafficking during cell migration

2020 ◽  
Author(s):  
Gabrielle Larocque ◽  
Penelope J. La-Borde ◽  
Beverley J. Wilson ◽  
Nicholas I. Clarke ◽  
Daniel J. Moore ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Surface ◽  
Membrane Trafficking ◽  
Surface Proteins ◽  
Migration And Invasion ◽  
Rab Gtpase ◽  
Surface Receptors ◽  
C Terminus ◽  
Transport Vesicle ◽  
Important Regulator

Membrane traffic is an important regulator of cell migration through the endocytosis and recycling of cell surface receptors such as integrin heterodimers. Intracellular nanovesicles (INVs), are a recently identified class of transport vesicle that are involved in multiple membrane trafficking steps including the recycling pathway. The only known marker for INVs is Tumor Protein D54 (TPD54/TPD52L2), a member of the TPD52-like protein family. Overexpression of TPD52-like family proteins in cancer has been linked to poor prognosis and an aggressive metastatic phenotype which suggests cell migration may be altered under these conditions. Here we show that TPD54 associates with INVs by directly binding high curvature membrane via a conserved positively charged motif in its C-terminus. We describe how other members of the TPD52-like family are also associated with INVs and we document the Rab GTPase complement of all INVs. Depletion of TPD52-like proteins inhibits cell migration and invasion; and we show that this is likely due to altered integrin recycling. Our study highlights the involvement of INVs in the trafficking of cell surface proteins to generate biologically important outputs in health and disease.

scholarly journals Src42A required for collective border cell migration in vivo

2017 ◽  
Author(s):  
Yasmin Sallak ◽  
Alba Yurani Torres ◽  
Hongyan Yin ◽  
Denise Montell
Keyword(s):  
Cell Migration ◽  
Cell Junctions ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Border Cell Migration ◽  
And Migration ◽  
Drosophila Ovary ◽  
E Cadherin

AbstractThe tyrosine kinase Src is over-expressed in numerous human cancers and is associated with poor prognosis. While Src has been extensively studied, its contributions to collective cell migration in vivo remain incompletely understood. Here we show that Src42A, but not Src64, is required for the specification and migration of the border cells in the Drosophila ovary, a well-developed and genetically tractable in vivo cell migration model. We found active Src42A enriched at border cell/nurse cell interfaces, where E-cadherin is less abundant, and depleted from border cell/border cell and border cell/polar cell junctions where E-cadherin is more stable, whereas total Src42A protein co-localizes with E-cadherin. Over-expression of wild type Src42A mislocalized Src activity and prevented border cell migration. Constitutively active or kinase dead forms of Src42A also impeded border cells. These findings establish border cells as a model for investigating the mechanisms of action of Src in cooperative, collective, cell-on-cell migration in vivo.

scholarly journals Local RNA translation controls cell migration and Rab GTPase function

2020 ◽  
Author(s):  
Konstadinos Moissoglu ◽  
Michael Stueland ◽  
Alexander N. Gasparski ◽  
Tianhong Wang ◽  
Lisa M. Jenkins ◽  
...  
Keyword(s):  
Cell Migration ◽  
Membrane Trafficking ◽  
Protein Function ◽  
Mammalian Cells ◽  
Distribution Patterns ◽  
Rna Localization ◽  
Rab Gtpase ◽  
Rna Translation ◽  
Specific Distribution ◽  
Promote Cell Migration

ABSTRACTNumerous RNAs exhibit specific distribution patterns in mammalian cells. However, the functional and mechanistic consequences are relatively unknown. We investigate here the functional role of RNA localization at cellular protrusions of mesenchymal migrating cells, using as a model the RAB13 RNA, which encodes a GTPase important for vesicle-mediated membrane trafficking. While RAB13 RNA is enriched at peripheral protrusions, the expressed protein is concentrated perinuclearly. By specifically preventing RAB13 RNA localization, we show that peripheral RAB13 translation is not important for the overall distribution of the RAB13 protein, or its ability to associate with membranes, but is required for full activation of the GTPase and for efficient cell migration. This effect is mediated by a co-translational association of RAB13 with the exchange factor RABIF. Our results indicate that RAB13-RABIF association at the periphery is required for directing RAB13 GTPase activity to promote cell migration. Thus, translation of RAB13 in specific subcellular environments imparts the protein with distinct properties and highlights a means of controlling protein function through local RNA translation.

scholarly journals Protein phosphatase 1 activity controls a balance between collective and single cell modes of migration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yujun Chen ◽  
Nirupama Kotian ◽  
George Aranjuez ◽  
Lin Chen ◽  
C Luke Messer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Protein Phosphatase ◽  
Single Cells ◽  
Cell Junctions ◽  
Protein Phosphatase 1 ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
And Migration

Collective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at individual internal border cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.

scholarly journals Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration

2019 ◽  
Author(s):  
Yujun Chen ◽  
Nirupama Kotian ◽  
George Aranjuez ◽  
Lin Chen ◽  
C. Luke Messer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Single Cell ◽  
Protein Phosphatase ◽  
Single Cells ◽  
Cell Junctions ◽  
Protein Phosphatase 1 ◽  
Collective Cell Migration ◽  
Border Cells ◽  
Border Cell ◽  
Cell Cell

AbstractCollective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at internal cell-cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.

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