Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

Marei, Hadir; Carpy, Alejandro; Woroniuk, Anna; Vennin, Claire; White, Gavin R M; Timpson, Paul; Maček, Boris; Malliri, Angeliki

doi:10.1038/ncomms10664

Cited by 69 publications

(121 citation statements)

References 70 publications

(97 reference statements)

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“…Second harmonic generation (SHG) imaging (31) and polarized light microscopy of picrosirius red staining (32, 33) of contracted collagen matrices revealed a reduction in fibrillar collagen coverage upon ROCK inhibition compared to control (Fig. 1, B to D, and fig.…”

Section: Resultsmentioning

confidence: 97%

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Vennin¹,

Chin²,

Warren³

et al. 2017

Sci. Transl. Med.

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222

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The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or “priming,” using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

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Section: Resultsmentioning

confidence: 97%

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Vennin¹,

Chin²,

Warren³

et al. 2017

Sci. Transl. Med.

Self Cite

222

240

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“…This leads to the remodelling of peripheral actin filaments in endothelial cells 89 . Another example is the RAC GEF P-REX1, which brings RAC1 together with its target FLI1 (friend leukaemia integration 1 transcription factor) to stimulate cell migration 90 . Similarly, DOCK1 is recruited to sites of developing cell-cell contacts by ELMO2 (engulfment and cell motility protein 2) 91 .…”

Section: Wave Regulatory Complexmentioning

confidence: 99%

Regulating Rho GTPases and their regulators

Hodge

Ridley²

2016

Nat Rev Mol Cell Biol

701

657

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Rho GTPases regulate cytoskeletal and cell adhesion dynamics and thereby coordinate a wide range of cellular processes, including cell migration, cell polarity and cell cycle progression. Most Rho GTPases cycle between a GTP-bound active conformation and a GDP-bound inactive conformation to regulate their ability to activate effector proteins and to elicit cellular responses. However, it has become apparent that Rho GTPases are regulated by post-translational modifications and the formation of specific protein complexes, in addition to GTP-GDP cycling. The canonical regulators of Rho GTPases - guanine nucleotide exchange factors, GTPase-activating proteins and guanine nucleotide dissociation inhibitors - are regulated similarly, creating a complex network of interactions to determine the precise spatiotemporal activation of Rho GTPases.

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“…It has been shown that activation of Rac1 is regulated by guanine nucleotide exchange factors (GEFs) [26]. To determine which exchange factors activate Rac1 downstream of autocrine VEGF and IL-8, we first investigated the endogenous expression of candidate Rac1 GEFs (Vav2, Tiam1, β-PIX, Sos-1 and DOCK180) in HUVECs.…”

Section: Resultsmentioning

confidence: 99%

“…Like all GTPases, the Rac1 is under tight spatial control, which is mediated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that catalyse GTP exchange and hydrolysis, respectively [23]. Specific GEF allows Rac1 to be activated in specific signal transduction pathways and coordinate more elaborate responses to specific demands at localized cellular sites [26, 42]. In this study, we identified the exchange factor Vav2 as mediating autocrine VEGF and IL-8 signaling to Rac1.…”

Section: Discussionmentioning

confidence: 99%

“…There are 2 distinct families of Rho GEFs with 11 members in human [23]. They function upstream of Rac1 and promote Rac1-dependent cell migration [25, 26]. However, despite the abundance and importance of these GEFs in the spatio-temporal control of Rac1 activation, little is known about their implication during autocrine growth factors and cytokines induced endothelial cell migration.…”

Section: Introductionmentioning

confidence: 99%

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Autocrine VEGF and IL-8 Promote Migration via Src/Vav2/Rac1/PAK1 Signaling in Human Umbilical Vein Endothelial Cells

Li¹,

Zhou²,

Jiang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Pro-angiogenic factors VEGF and IL-8 play a major role in modulating the migratory potential of endothelial cells. The goal of this study was to investigate the effect of autocrine VEGF and IL-8 in the form of self-conditioned medium (CM) on human umbilical vein endothelial cells (HUVECs). Methods: Enzyme-linked immunosorbent assay (ELISA) examined the automatic secretion of VEGF and IL-8 protein by HUVECs. Western blot, small interfering RNA (siRNA), pulldown and Transwell assays were used to explore the role and the mechanism of autocrine VEGF and IL-8 in migration of HUVECs. Results: Neutralizing VEGF and IL-8 in CM significantly abrogated CM-induced migration of HUVECs. Autocrine VEGF and IL-8 increased Src phosphorylation, Rac1 activity and PAK1 phosphorylation in a time dependent manner. Additionally, blocking Rac1 activity with Rac1 siRNA largely abolished autocrine VEGF and IL-8-induced cell migration. Vav2 siRNA suppressed autocrine VEGF and IL-8-induced Rac1 activation and cell migration. Furthermore, blocking Src signaling with PP2, a specific inhibitor for Src, markedly prevented autocrine VEGF and IL-8-induced Vav2 and Rac1 activation as well as consequently cell migration. PAK1 siRNA also significantly abolished autocrine VEGF and IL-8-induced cell migration. Conclusions: We demonstrated for the first time that autocrine VEGF and IL-8 promoted endothelial cell migration via the Src/Vav2/Rac1/PAK1 signaling pathway. This finding reveals the molecular mechanism in the increase of endothelial cell migration induced by autocrine growth factors and cytokines, which is expected to provide a novel therapeutic target in vascular diseases.

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Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

Cited by 69 publications

References 70 publications

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Regulating Rho GTPases and their regulators

Autocrine VEGF and IL-8 Promote Migration via Src/Vav2/Rac1/PAK1 Signaling in Human Umbilical Vein Endothelial Cells

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