ArticleThe Journal of biological chemistry2016
Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor: EFFECT ON PKA LOCALIZATION AND P-Rex1 SIGNALING.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 43 citations in OpenAlex.
- Protein kinase a regulates cyclooxygenase-2 expression through the RNA-binding proteins HuR and TTP.The Journal of biological chemistry · 2026Article
- Regulation of Rho guanine nucleotide exchange factor 3 by phosphorylation in the PH domain.iScience · 2025Article
- Understanding P-Rex regulation: structural breakthroughs and emerging perspectives.Biochemical Society transactions · 2024Review
- Article
- Betaglycan sustains HGF/Met signaling in lung cancer and endothelial cells promoting cell migration and tumor growth.Heliyon · 2024Article
- Structural and dynamic changes in P-Rex1 upon activation by PIPbioRxiv : the preprint server for biology · 2024Article
- Review
- Oncogenic Gαq activates RhoJ through PDZ-RhoGEF.International journal of molecular sciences · 2023Article
- Small-molecule inhibitors of P-Rex guanine-nucleotide exchange factors.Small GTPases · 2022Article
- Protein Kinase A in cellular migration-Niche signaling of a ubiquitous kinase.Frontiers in molecular biosciences · 2022Review
- P-Rex1 Signaling Hub in Lower Grade Glioma Patients, Found byFrontiers in oncology · 2022Article
- Article
- The first DEP domain of the RhoGEF P-Rex1 autoinhibits activity and contributes to membrane binding.The Journal of biological chemistry · 2020Article
- Feedback regulation between phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1 and transforming growth factor β1 and prognostic value in gastric cancer.World journal of gastroenterology · 2020Article
- Protein kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis.Molecular biology of the cell · 2020Article
- Cryo-electron microscopy structure and analysis of the P-Rex1-Gβγ signaling scaffold.Science advances · 2019Article
- Protumoral bone marrow-derived cells migrate via Gβγ-dependent signaling pathways and exhibit a complex repertoire of RhoGEFs.Journal of cell communication and signaling · 2019Article
- "A-kinase" regulator runs amok to provide a paradigm shift in cAMP signaling.The Journal of biological chemistry · 2019Article
- cAMP-dependent activation of the Rac guanine exchange factor P-REX1 by type I protein kinase A (PKA) regulatory subunits.The Journal of biological chemistry · 2019Article
- Gβγ signaling to the chemotactic effector P-REX1 and mammalian cell migration is directly regulated by GαThe Journal of biological chemistry · 2019Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
Morphology of migrating cells is regulated by Rho GTPases and fine-tuned by protein interactions and phosphorylation. PKA affects cell migration potentially through spatiotemporal interactions with regulators of Rho GTPases. Here we show that the endogenous regulatory (R) subunit of type I PKA interacts with P-Rex1, a Rac guanine nucleotide exchange factor that integrates chemotactic signals. Type I PKA holoenzyme interacts with P-Rex1 PDZ domains via the CNB B domain of RIα, which when expressed by itself facilitates endothelial cell migration. P-Rex1 activation localizes PKA to the cell periphery, whereas stimulation of PKA phosphorylates P-Rex1 and prevents its activation in cells responding to SDF-1 (stromal cell-derived factor 1). The P-Rex1 DEP1 domain is phosphorylated at Ser-436, which inhibits the DH-PH catalytic cassette by direct interaction. In addition, the P-Rex1 C terminus is indirectly targeted by PKA, promoting inhibitory interactions independently of the DEP1-PDZ2 region. A P-Rex1 S436A mutant construct shows increased RacGEF activity and prevents the inhibitory effect of forskolin on sphingosine 1-phosphate-dependent endothelial cell migration. Altogether, these results support the idea that P-Rex1 contributes to the spatiotemporal localization of type I PKA, which tightly regulates this guanine exchange factor by a multistep mechanism, initiated by interaction with the PDZ domains of P-Rex1 followed by direct phosphorylation at the first DEP domain and putatively indirect regulation of the C terminus, thus promoting inhibitory intramolecular interactions. This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA.
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