Compartmentalisation of RAC1 signalling

Payapilly, Aishwarya; Malliri, Angeliki

doi:10.1016/j.ceb.2018.04.009

Cited by 74 publications

(62 citation statements)

References 68 publications

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“…Finally, we showed that the localization of Rac1 protein is at the leading edge of PC3 cells overexpressing Rac1 WT (in EGF‐stimulated cells) and Rac1 constitutively active (Figure 6C). These findings confirm that Rac1 needs to be bound to GTP, to be translocalized to the leading edge of migrating cells 38 . Thus, higher Rac1 activity in Rac1WT and Rac1Q61L cells caused Rac1 to localize at the leading edge, which in turn caused an increase in cell migration.…”

Section: Discussionsupporting

confidence: 70%

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Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

et al. 2020

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Background Mammalian target of rapamycin (mTOR) is a downstream substrate activated by PI3K/AKT pathway and it is essential for cell migration. It exists as two complexes: mTORC1 and mTORC2. mTORC1 is known to be regulated by active AKT, but the activation of mTORC2 is poorly understood. In this study, we investigated the roles and differential activation of the two mTOR complexes during cell migration in prostate cancer cells. Methods We used small interfering RNA to silence the expression of Rac1 and the main components of mTOR complexes (regulatory associated protein of mTOR [RAPTOR] and rapamycin‐insensitive companion of mTOR [RICTOR]) in LNCaP, DU145, and PC3 prostate cancer cell lines. We performed transwell migration assay to evaluate the migratory capability of the cells, and Western blot analysis to study the activation levels of mTOR complexes. Results Specific knockdown of RAPTOR and RICTOR caused a decrease of cell migration, suggesting their essential role in prostate cancer cell movement. Furthermore, epidermal growth factor (EGF) treatments induced the activation of both the mTOR complexes. Lack of Rac1 activity in prostate cancer cells blocked EGF‐induced activation of mTORC2, but had no effect on mTORC1 activation. Furthermore, the overexpression of constitutively active Rac1 resulted in significant increase in cell migration and activation of mTORC2 in PC3 cells, but had no effect on mTORC1 activation. Active Rac1 was localized in the plasma membrane and was found to be in a protein complex, with RICTOR, but not RAPTOR. Conclusion We suggest that EGF‐induced activation of Rac1 causes the activation of mTORC2 via RICTOR. This mechanism plays a critical role in prostate cancer cell migration.

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Section: Discussionsupporting

confidence: 70%

“…These findings confirm that Rac1 needs to be bound to GTP, to be translocalized to the leading edge of migrating cells. 38 Thus, higher Rac1 activity in Rac1WT and Rac1Q61L cells caused Rac1 to localize at the leading edge, which in turn caused an increase in cell migration.…”

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confidence: 97%

Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

et al. 2020

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“…Finally, we highlight proteins from our screen that interact with Rac1 Q61L and Rac1 P29S/ Q61L at specific regions within the cell ( Figure 2D). This follows recent literature showing diverse functions for Rac1 activity throughout the cell [37].…”

Section: Proteins That Bind Specifically To Active Rac1supporting

confidence: 87%

CYRI/ Fam49 Proteins Represent a New Class of Rac1 Interactors

Whitelaw

Lilla

Paul

et al. 2019

Communicative & Integrative Biology

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Fam49 proteins, now referred to as CYRI (CYFIP-related Rac Interactor), are evolutionarily conserved across many phyla. Their closest relative by amino acid sequence is CYFIP, as both proteins contain a domain of unknown function DUF1394. We recently showed that CYRI and the DUF1394 can mediate binding to Rac1 and evidence is building to suggest that CYRI plays important roles in cell migration, chemotaxis and pathogen entry into cells. Here we discuss how CYRI proteins fit into the current framework of the control of actin dynamics by positive and negative feedback loops containing Rac1, the Scar/WAVE Complex, the Arp2/3 Complex and branched actin. We also provide data regarding the interaction between Rac1 and CYRI in an unbiassed mass spectrometry screen for interactors of an active mutant of Rac1.

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“…This implies that the nuclear and cytoplasmic localisations may influence the conformation of SWAP70, which resides in both compartments [41]. Although we have not followed up this observation, it is potentially related to the recognised differential regulation of RAC1 In the nucleus [42]. The enrichment of F-actin, PIP 3 and active RAC1 has previously been observed at the leading edge of adherent cells during their directed migration [24,[43][44][45].…”

Section: Discussionmentioning

confidence: 79%

“…On the other hand, we do not interpret this and the lack of impact of the R230C phosphoinositide binding mutation to mean that PI3K is not involved in the conformational activation of SWAP70. Although we have not followed up this observation, it is potentially related to the recognised differential regulation of RAC1 In the nucleus [42]. We also suggest that the high-FRET subpopulation of SWAP70 revealed within these cells is likely to be the active, functionally significant pool capable of activating RAC1 and perhaps other GTPases.…”

Section: Discussionmentioning

confidence: 84%

SWAP70 undergoes dynamic conformational regulation at the leading edge of migrating cells

2019

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Rearrangements of the actin cytoskeleton are regulated in part by dynamic localised activation and inactivation of Rho family small GTPases. SWAP70 binds to and activates the small GTPase RAC1 as well as binding to filamentous actin and PIP3. We have developed an encoded biosensor, which uses Forster resonance energy transfer to reveal conformational changes in SWAP70 in live cells. SWAP70 adopts a distinct conformation at the plasma membrane, which in migrating glioma cells is enriched at the leading edge but does not always associate with its PIP3‐dependent translocation to the membrane. This supports a role for SWAP70 in positive feedback activation of RAC1 at sites of filamentous actin, PIP3 and active RAC1.

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Compartmentalisation of RAC1 signalling

Cited by 74 publications

References 68 publications

Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells

CYRI/ Fam49 Proteins Represent a New Class of Rac1 Interactors

SWAP70 undergoes dynamic conformational regulation at the leading edge of migrating cells

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