Light-mediated activation reveals a key role for Rac in collective guidance of cell movement in vivo

Wang, Xiaobo; He, Lili; Wu, Yi; Hahn, Klaus M.; Montell, Denise J.

doi:10.1038/ncb2061

Cited by 313 publications

(403 citation statements)

References 31 publications

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“…Furthermore, mammalian Tiam1, a GDP-to-GTP exchange factor (GEF) for Rac, has recently been shown to localize to endosomes, leading to the loading of active Rac at the plasma membrane through an endocytic-recycling cycle (34). Interestingly, we found a robust genetic interaction between Rab11 and Rac1, which directs border cell migration (22). Until now, two Rac-GEFs, myoblast city and elmo, have been involved in border cell migration, but not the Drosophila Tiam1 homolog still life (42).…”

Section: Discussionmentioning

confidence: 68%

“…Hence, we decided to search for a genetic interaction between Rab11 and the common downstream target of the RTK pathways. Rac1 was recently shown to be that common target and to be necessary for border cell migration (22,23). Indeed, we observed a strong synergetic effect between rab11 and two different mutant forms of rac1 (24): racL89 andracN17 (Fig.…”

Section: Trafficking Through the Early Endosome And The Recycling Endmentioning

confidence: 59%

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Spatial restriction of receptor tyrosine kinase activity through a polarized endocytic cycle controls border cell migration

Assaker

Ramel²,

Wculek³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

107

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Border cell migration is a stereotyped migration occurring during the development of the Drosophila egg chamber. During this process, a cluster composed of six to eight follicle cells migrates between nurse cells toward the oocyte. Receptor tyrosine kinases (RTKs) are enriched at the leading edge of the follicle cells and establish the directionality of their migration. Endocytosis has been shown to play a role in the maintenance of this polarization; however, the mechanisms involved are largely unknown. In this study, we show that border cell migration requires the function of the small GTPases Rab5 and Rab11 that regulate trafficking through the early and the recycling endosome, respectively. Expression of a dominant negative form of rab11 induces a loss of the polarization of RTK activity, which correlates with a severe migration phenotype. In addition, we demonstrate that the exocyst component Sec15 is distributed in structures that are polarized during the migration process in a Rab11-dependent manner and that the down-regulation of different subunits of the exocyst also affects migration. Together, our data demonstrate a fundamental role for a plasma membrane-endosome trafficking cycle in the maintenance of active RTK at the leading edge of border cells during their migration.

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Section: Discussionmentioning

confidence: 68%

Section: Trafficking Through the Early Endosome And The Recycling Endmentioning

confidence: 59%

Spatial restriction of receptor tyrosine kinase activity through a polarized endocytic cycle controls border cell migration

Assaker

Ramel²,

Wculek³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

107

View full text Add to dashboard Cite

show abstract

“…Localization and signaling motifs can be linked to either domain, allowing spatial-temporal control of protein function. We used our combined system to study the effects of a rapidly induced intracellular gradient of activated Rac, which is an important regulator of cell polarity (27) and has been shown previously to induce migration when locally activated (9,(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Synthetic spatially graded Rac activation drives cell polarization and movement

Lin

Holmes

Wang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

101

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Migrating cells possess intracellular gradients of active Rho GTPases, which serve as central hubs in transducing signals from extracellular receptors to cytoskeletal and adhesive machinery. However, it is unknown whether shallow exogenously induced intracellular gradients of Rho GTPases are sufficient to drive cell polarity and motility. Here, we use microfluidic control to generate gradients of a small molecule and thereby directly induce linear gradients of active, endogenous Rac without activation of chemotactic receptors. Gradients as low as 15% were sufficient not only to trigger cell migration up the chemical gradient but to induce both cell polarization and repolarization. Cellular response times were inversely proportional to the steepness of Rac inducer gradient in agreement with a mathematical model, suggesting a function for chemoattractant gradient amplification upstream of Rac. Increases in activated Rac levels beyond a well-defined threshold augmented polarization and decreased sensitivity to the imposed gradient. The threshold was governed by initial cell polarity and PI3K activity, supporting a role for both in defining responsiveness to Rac activation. Our results reveal that Rac can serve as a starting point in defining cell polarity. Furthermore, our methodology may serve as a template to investigate processes regulated by intracellular signaling gradients.cell signaling | synthetic biology | chemotaxis | signal transduction

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“…In this study, a combination of PA-Rac1 and Raichu-Rac1 biosensor showed that Rac1 activation regulates the directionality of border cell migration in Drosophila embryos. 80 It was found that the directionality of the cells depends on the asymmetric localization of Rac and that the establishment of asymmetry is dependent on the guidance receptors, PVR and EGFR. Furthermore, Rac1 activity has been observed in migrating germ cells in developing zebrafish embryos.…”

Section: Rac Gtpases: Lighting Up the Lamellipodiamentioning

confidence: 99%

“…This tool has been effectively employed both in cellular and multicellular models to demonstrate that activation of Rac1 is required for directional cell migration. 75,[79][80][81][82] Recently a number of studies have combined the use of biosensors to monitor the activity of Rac1 with the manipulation of this protein by specific photoactivation have been used to determine the functions of Rac1 in Drosophila border cell migration and tumor cell invasion. 74,83 Studies such as these which combine different microscopy and optical approaches to dissect the mechanism of GTPase signaling in different contexts will pave the way for a complete understanding of the biology of these proteins.…”

Section: Rac Gtpases: Lighting Up the Lamellipodiamentioning

confidence: 99%