P-Rex1

Hornigold, Kirsti; Tsonou, Elpida; Pantarelli, Chiara; Welch, Heidi C. E.

doi:10.1007/978-3-319-67199-4_101726

Cited by 3 publications

(6 citation statements)

References 20 publications

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“…It is directly activated by PIP 3 and also by the Gβγ subunits of heterotrimeric G proteins, which are released upon activation of GPCRs. In addition, various phosphorylation events modulate its activity (Figure ). PIP 3 and Gβγ subunits also recruit this GEF to the plasma membrane, possibly in conjunction with the GPCR‐adaptor protein Norbin, although this remains to be tested in neutrophils .…”

Section: Rac‐gtpases and Their Gefs In Neutrophilsmentioning

confidence: 99%

Rac‐GTPases and Rac‐GEFs in neutrophil adhesion, migration and recruitment

Pantarelli

Welch

2018

Eur J Clin Investigation

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Rac-GTPases and their Rac-GEF activators play important roles in the recruitment and host defence functions of neutrophils. These proteins control the activation of adhesion molecules and the cytoskeletal dynamics that enable the adhesion, migration and tissue recruitment of neutrophils. They also regulate the effector functions that allow neutrophils to kill bacterial and fungal pathogens, and to clear debris. This review focuses on the roles of Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment.

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Section: Rac‐gtpases and Their Gefs In Neutrophilsmentioning

confidence: 99%

Rac‐GTPases and Rac‐GEFs in neutrophil adhesion, migration and recruitment

Pantarelli

Welch

2018

Eur J Clin Investigation

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“…P-Rex1 is a guanine-nucleotide exchange factor (GEF) for Rac-type small guanine nucleotide-binding proteins (GTPases; Rac1, Rac2, Rac3, and RhoG) [ 1 , 2 , 3 ]. As a typical activator of Rac proteins, P-Rex1 controls cell morphology, adhesion, and chemotaxis through cytoskeletal dynamics, as well as reactive oxygen species (ROS) production, gene expression, and cell survival [ 2 , 3 ]. P-Rex1 is primarily expressed in leukocytes and in the nervous system, but is found at lower levels in many cell types [ 1 , 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…As a typical activator of Rac proteins, P-Rex1 controls cell morphology, adhesion, and chemotaxis through cytoskeletal dynamics, as well as reactive oxygen species (ROS) production, gene expression, and cell survival [ 2 , 3 ]. P-Rex1 is primarily expressed in leukocytes and in the nervous system, but is found at lower levels in many cell types [ 1 , 2 , 3 ]. P-Rex1 function has mostly been studied in leukocytes and platelets, where this GEF is important for a range of proinflammatory and immune functions, including adhesion, migration, and ROS production [ 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…P-Rex1 is also known for controlling the proliferation and migration of melanocytes during development [ 15 , 16 ], the morphology and migration of fibroblasts [ 17 , 18 , 19 ], the migration, secretory, and barrier functions of endothelial cells under proangiogenic or inflammatory conditions [ 20 , 21 , 22 ], and the glucose uptake and thermogenic capacities of adipocytes [ 23 , 24 ]. In addition, P-Rex1 levels are commonly deregulated in many types of cancer, including melanoma, breast, and prostate cancer, promoting tumour growth or metastasis [ 2 , 3 , 15 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…P-Rex1 is a Dbl-type Rac-GEF with multiple domains that serve to regulate its activity and subcellular localisation [ 2 , 3 ]. The GEF activity of P-Rex1 is directly activated by the Gβγ subunits of heterotrimeric G proteins downstream of G protein-coupled receptors (GPCRs).…”

Section: Introductionmentioning

confidence: 99%

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P-Rex1 Controls Sphingosine 1-Phosphate Receptor Signalling, Morphology, and Cell-Cycle Progression in Neuronal Cells

Hampson

Tsonou

Baker

et al. 2021

Cells

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P-Rex1 is a guanine-nucleotide exchange factor (GEF) that activates Rac-type small G proteins in response to the stimulation of a range of receptors, particularly G protein-coupled receptors (GPCRs), to control cytoskeletal dynamics and other Rac-dependent cell responses. P-Rex1 is mainly expressed in leukocytes and neurons. Whereas its roles in leukocytes have been studied extensively, relatively little is known about its functions in neurons. Here, we used CRISPR/Cas9-mediated P-Rex1 deficiency in neuronal PC12 cells that stably overexpress the GPCR S1PR1, a receptor for sphingosine 1-phosphate (S1P), to investigate the role of P-Rex1 in neuronal GPCR signalling and cell responses. We show that P-Rex1 is required for the S1P-stimulated activation of Rac1 and Akt, basal Rac3 activity, and constitutive cAMP production in PC12-S1PR1 cells. The constitutive cAMP production was not due to increased expression levels of major neuronal adenylyl cyclases, suggesting that P-Rex1 may regulate adenylyl cyclase activity. P-Rex1 was required for maintenance of neurite protrusions and spreading in S1P-stimulated PC12-S1PR1 cells, as well as for cell-cycle progression and proliferation. In summary, we identified novel functional roles of P-Rex1 in neuronal Rac, Akt and cAMP signalling, as well as in neuronal cell-cycle progression and proliferation.

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Small-molecule inhibitors of P-Rex guanine-nucleotide exchange factors

et al. 2022

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P-Rex1 and P-Rex2 are guanine-nucleotide exchange factors (GEFs) that activate Rac small GTPases in response to the stimulation of G protein-coupled receptors and phosphoinositide 3-kinase. P-Rex Rac-GEFs regulate the morphology, adhesion and migration of various cell types, as well as reactive oxygen species production and cell cycle progression. P-Rex Rac-GEFs also have pathogenic roles in the initiation, progression or metastasis of several types of cancer. With one exception, all P-Rex functions are known or assumed to be mediated through their catalytic Rac-GEF activity. Thus, inhibitors of P-Rex Rac-GEF activity would be valuable research tools. We have generated a panel of small-molecule P-Rex inhibitors that target the interface between the catalytic DH domain of P-Rex Rac-GEFs and Rac. Our best-characterized compound, P-Rex inhibitor 1 (PREX-in1), blocks the Rac-GEF activity of full-length P-Rex1 and P-Rex2, and of their isolated catalytic domains, in vitro at low-micromolar concentration, without affecting the activities of several other Rho-GEFs. PREX-in1 blocks the P-Rex1 dependent spreading of PDGF-stimulated endothelial cells and the production of reactive oxygen species in fMLP-stimulated mouse neutrophils. Structure-function analysis revealed critical structural elements of PREX-in1, allowing us to develop derivatives with increased efficacy, the best with an IC 50 of 2 µM. In summary, we have developed PREX-in1 and derivative small-molecule compounds that will be useful laboratory research tools for the study of P-Rex function. These compounds may also be a good starting point for the future development of more sophisticated drug-like inhibitors aimed at targeting P-Rex Rac-GEFs in cancer.

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P-Rex1

Cited by 3 publications

References 20 publications

Rac‐GTPases and Rac‐GEFs in neutrophil adhesion, migration and recruitment

Rac‐GTPases and Rac‐GEFs in neutrophil adhesion, migration and recruitment

P-Rex1 Controls Sphingosine 1-Phosphate Receptor Signalling, Morphology, and Cell-Cycle Progression in Neuronal Cells

Small-molecule inhibitors of P-Rex guanine-nucleotide exchange factors

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