Biology subjects

Hornigold, D. C.

Publications and source records attributed to Hornigold, D. C..

3 recordsLinked to original sources

bioRxiv2025

Prex1 controls glucose homeostasis by limiting glucose uptake and mitochondrial metabolism in liver through GEF-independent regulation of Gpr21

We investigated the roles of Rac guanine-nucleotide factor (Rac-GEF) Prex1 in glucose homeostasis using Prex1-/- and catalytically-inactive Prex1GD mice. Prex1 maintains fasting blood glucose levels and insulin sensitivity through its Rac-GEF activity but limits glucose clearance independently of its catalytic activity, throughout ageing. Prex1-/-mice on high-fat diet are protected from developing diabetes. The increased glucose clearance in Prex1-/- mice stems from constitutively enhanced hepatic glucose uptake. Prex1 limits Glut2 surface levels, mitochondrial membrane potential and mitochondrial ATP production, and controls mitochondrial morphology in hepatocytes, independently of its catalytic activity. Prex1 limits GPCR trafficking through an adaptor function, and we identify here the inhibitory orphan GPCR Gpr21 as a Prex1 target. The Gpr21-mediated blockade of glucose uptake and mitochondrial ATP production in hepatocytes requires Prex1. We propose that Prex1 limits glucose clearance by maintaining Gpr21 at the hepatocyte surface, thus limiting hepatic glucose uptake and metabolism. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/648781v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@110e660org.highwire.dtl.DTLVardef@84c0c3org.highwire.dtl.DTLVardef@18b8319org.highwire.dtl.DTLVardef@4bfde0_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

P-Rex1 Limits the Agonist-Induced Internalisation of GPCRs Independently of its Rac-GEF Activity

The Rac-GEF P-Rex1 mediates GPCR signalling by activating the small GTPase Rac. We show here that P-Rex1 also controls GPCR trafficking. P-Rex1 inhibits the agonist-stimulated internalisation of the GPCR S1PR1 independently of its Rac-GEF activity, through its PDZ, DEP and IP4P domains. P-Rex1 also limits the agonist-induced trafficking of CXCR4, PAR4, and GLP1R, but does not control steady-state GPCR levels, nor the agonist-induced internalisation of the RTKs PDGFR and EGFR. P-Rex1 blocks the phosphorylation required for GPCR internalisation. P-Rex1 binds Grk2, both in vitro and in cells, but does not appear to regulate Grk2 activity. We propose that P-Rex1 limits the agonist-induced internalisation of GPCRs through its interaction with Grk2 to maintain high levels of active GPCR at the plasma membrane. Therefore, P-Rex1 plays a dual role in promoting GPCR responses, by controlling GPCR trafficking through an adaptor function as well as by mediating GPCR signalling through its Rac-GEF activity. HighlightsO_LIP-Rex1 controls GPCR trafficking, independently of its Rac-GEF activity C_LIO_LIP-Rex1 limits the agonist-induced internalisation of S1PR1, CXCR4, PAR4 and GLP1R C_LIO_LIP-Rex1 does not control steady-state GPCR levels, or PDGFR and EGFR trafficking C_LIO_LIP-Rex1 binds Grk2 and inhibits the phosphorylation required for GPCR internalisation C_LI eTOC blurbP-Rex1 activates Rac downstream of GPCRs to regulate processes ranging from innate immunity to neuronal plasticity, its deregulation contributing to cancer. Here, Baker et al. show that P-Rex1 also controls GPCR trafficking, limiting agonist-induced GPCR internalisation through an adaptor function. Thus, P-Rex1 promotes GPCR responses in a dual manner. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/648762v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@20e1e2org.highwire.dtl.DTLVardef@cdd416org.highwire.dtl.DTLVardef@11f2a35org.highwire.dtl.DTLVardef@10c2b49_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

A targetable PREX2/RAC1/PI3Kβ signalling axis confers resistance to clinically relevant therapeutic approaches in melanoma

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, with mutations of its upstream regulator, the RAC-GEF PREX2, also commonly detected. Crucially, RAC1 mutations are associated with resistance to BRAF-targeting therapies. Despite the role of its homologue PREX1 in melanomagenesis, and evidence that some truncating PREX2 mutations drive increased RAC1 activity, no hotspot mutations have been identified, and the impact of PREX2 mutation remains contentious. Here, we use genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. We show that while PREX2 is dispensable for the initiation and progression of melanoma, its loss confers sensitivity to clinically relevant therapeutics. Importantly, genetic and pharmacological targeting of the RAC1 effector kinase PI3K{beta} phenocopies PREX2 loss, sensitizing our model systems to therapy. Our data reveal a druggable PREX2/RAC1/PI3K{beta} signalling axis in BRAF-mutant melanoma that could be exploited clinically. Statement of SignificanceMetastatic melanoma remains both a clinical problem, and an opportunity for therapeutic benefit. Co-targeting of the MAPK pathway and the PREX2/RAC1/PI3K{beta} has remarkable efficacy and outperforms monotherapy MAPK targeting in vivo.

cancer biology↗