P-Rex2

Tsonou, Elpida; Pantarelli, Chiara; Hornigold, Kirsti; Welch, Heidi

doi:10.1007/978-3-319-67199-4_101727

Cited by 1 publication

(2 citation statements)

References 34 publications

(8 reference statements)

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“…P-Rex1 also controls various functions of macrophages, platelets, endothelial cells, fibroblasts, melanoblasts, adipose cells and neurons that are associated with cytoskeletal dynamics, including morphology, adhesion, migration and secretory processes, as well as being involved in cell-cycle control [ 5 , 6 ]. The cellular functions of P-Rex2 have been studied less, but the protein is known for regulating the morphology and synaptic plasticity of cerebellar neurons, whereas P-Rex2b, a C-terminally truncated splice variant, regulates the migration of endothelial cells [ 5 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Another important mechanism of P-Rex1 regulation is phosphorylation by cAMP-dependent kinase (PKA), which inhibits P-Rex1 activity by stabilizing the autoinhibited conformation [ 34 , 35 ]. In addition, P-Rex activity is both positively and negatively modulated through phosphorylations controlled by various protein kinases and phosphatases [ 5 , 6 , 15 ], and P-Rex1 membrane localization is promoted by the GPCR-adaptor protein Norbin [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

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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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