ArticleProceedings of the National Academy of Sciences of the United States of America2013
Protein kinase C-theta (PKCθ) phosphorylates and inhibits the guanine exchange factor, GIV/Girdin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 39 citations in OpenAlex.
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- Elevated Kallistatin Induces Myosteatosis and Exercise Intolerance by Antagonizing AdipoR1-Mediated AMPK Signalling.Journal of cachexia, sarcopenia and muscle · 2026Article
- Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif.The Journal of biological chemistry · 2024Review
- Identification of Six Diagnostic Biomarkers for Chronic Lymphocytic Leukemia Based on Machine Learning Algorithms.Journal of oncology · 2022Article
- Article
- The Emerging Function of PKCtheta in Cancer.Biomolecules · 2021Review
- Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance.International journal of molecular sciences · 2020Review
- Ric-8A, a GEF, and a Chaperone for G Protein α-Subunits: Evidence for the Two-Faced Interface.BioEssays : news and reviews in molecular, cellular and developmental biology · 2020Article
- Structural basis for GPCR-independent activation of heterotrimeric Gi proteins.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- A predictive computational model reveals that GIV/girdin serves as a tunable valve for EGFR-stimulated cyclic AMP signals.Molecular biology of the cell · 2019Article
- Mechanisms of Insulin Action and Insulin Resistance.Physiological reviews · 2018Review
- The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block.Cell cycle (Georgetown, Tex.) · 2017Review
- YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells.Cell cycle (Georgetown, Tex.) · 2017Article
- Biochemical, Biophysical and Cellular Techniques to Study the Guanine Nucleotide Exchange Factor, GIV/Girdin.Current protocols in chemical biology · 2016Article
- Substrate Affinity Differentially Influences Protein Kinase C Regulation and Inhibitor Potency.The Journal of biological chemistry · 2016Article
- GIV/Girdin activates Gαi and inhibits Gαs via the same motif.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space, and time.BioEssays : news and reviews in molecular, cellular and developmental biology · 2016Review
- The untapped potential of tyrosine-based G protein signaling.Pharmacological research · 2016Review
- Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins.Molecular biology of the cell · 2015Article
- Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity.Molecular biology of the cell · 2015Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Gα-interacting, vesicle-associated protein (GIV/Girdin) is a multidomain signal transducer that enhances PI3K-Akt signals downstream of both G-protein-coupled receptors and growth factor receptor tyrosine kinases during diverse biological processes and cancer metastasis. Mechanistically, GIV serves as a non-receptor guanine nucleotide exchange factor (GEF) that enhances PI3K signals by activating trimeric G proteins, Gαi1/2/3. Site-directed mutations in GIV's GEF motif disrupt its ability to bind or activate Gi and abrogate PI3K-Akt signals; however, nothing is known about how GIV's GEF function is regulated. Here we report that PKCθ, a novel protein kinase C, down-regulates GIV's GEF function by phosphorylating Ser(S)1689 located within GIV's GEF motif. We demonstrate that PKCθ specifically binds and phosphorylates GIV at S1689, and this phosphoevent abolishes GIV's ability to bind and activate Gαi. HeLa cells stably expressing the phosphomimetic mutant of GIV, GIV-S1689→D, are phenotypically identical to those expressing the GEF-deficient F1685A mutant: Actin stress fibers are decreased and cell migration is inhibited whereas cell proliferation is triggered, and Akt (a.k.a. protein kinase B, PKB) activation is impaired downstream of both the lysophosphatidic acid receptor, a G-protein-coupled receptor, and the insulin receptor, a receptor tyrosine kinase. These findings indicate that phosphorylation of GIV by PKCθ inhibits GIV's GEF function and generates a unique negative feedback loop for downregulating the GIV-Gi axis of prometastatic signaling downstream of multiple ligand-activated receptors. This phosphoevent constitutes the only regulatory pathway described for terminating signaling by any of the growing family of nonreceptor GEFs that modulate G-protein activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.