P-Rex1 Controls Sphingosine 1-Phosphate Receptor Signalling, Morphology, and Cell-Cycle Progression in Neuronal Cells
AuthorsHampson, Elizabeth; email: Elizabeth.Hampson@babraham.ac.uk
Tsonou, Elpida; email: firstname.lastname@example.org
Baker, Martin J.; orcid: 0000-0002-9743-6294; email: email@example.com
Hornigold, David C.; orcid: 0000-0002-3354-2768; email: David.Hornigold@astrazeneca.com
Hubbard, Roderick E.; email: firstname.lastname@example.org
Massey, Andrew; email: email@example.com
Welch, Heidi C. E.; orcid: 0000-0001-7865-7000; email: firstname.lastname@example.org
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AbstractP-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.
CitationCells, volume 10, issue 9, page e2474
DescriptionFrom MDPI via Jisc Publications Router
History: accepted 2021-09-15, pub-electronic 2021-09-18
Publication status: Published
Funder: Biotechnology and Biological Sciences Research Council; Grant(s): BB/P013384/1
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