Title: The Guanine-Nucleotide Exchange Factor (GEF) P‑Rex1 is Activated by Protein Phosphatase 1α (PP1α)
Authors: Barber, Mark A ×
Hendrickx, Annick
Beullens, Monique
Ceulemans, Hugo
Oxley, David
Thelen, Sylvia
Thelen, Marcus
Bollen, Mathieu
Welch, Heidi C E #
Issue Date: Jan-2012
Publisher: Published by Portland Press on behalf of the Biochemical Society
Series Title: Biochemical Journal vol:443 pages:173-183
Abstract: P‑Rex1 is a guanine-nucleotide exchange factor (GEF) for the small G protein Rac that is activated by PIP3 and Gbg subunits and inhibited by PKA. Here, we show that Protein Phosphatase 1a (PP1a) binds P‑Rex1 through an RVxF-type docking motif. PP1a activates P‑Rex1 directly in vitro, both independently of and additively to PIP3 and Gbg. PP1a also substantially activates P‑Rex1 in vivo, both in basal and PDGF- or LPA-stimulated cells. The phosphatase activity of PP1a is required for P‑Rex1 activation. PP1b, a close homologue of PP1a, is also able to activate P‑Rex1, but less effectively. PP1a stimulates P-Rex1-mediated, Rac-dependent changes in endothelial cell morphology. Mass spectrometric analysis of wild-type P‑Rex1 and a PP1a-binding deficient mutant revealed that endogenous PP1a dephosphorylates P‑Rex1 on at least three residues, S834, S1001 and S1165. Site-directed mutagenesis of S1165 to alanine caused activation of P-Rex1 to a similar degree as did PP1a, confirming S1165 as a dephosphorylation site important in regulating P‑Rex1 Rac-GEF activity. In summary, we have identified a novel mechanism for direct activation of P‑Rex1 through PP1a-dependent dephosphorylation.
ISSN: 0264-6021
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Biosignaling & Therapeutics
Biochemistry, Molecular and Structural Biology Section
× corresponding author
# (joint) last author

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