ArticleProceedings of the National Academy of Sciences of the United States of America2012
Functional characterization of the guanine nucleotide exchange factor (GEF) motif of GIV protein reveals a threshold effect in signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif.The Journal of biological chemistry · 2024Review
- Rapamycin as a Potential Alternative Drug for Squamous Cell Gingiva Carcinoma (Ca9-22): A Focus on Cell Cycle, Apoptosis and Autophagy Genetic Profile.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Article
- Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer.Life science alliance · 2020Article
- DAPLE protein inhibits nucleotide exchange on GαThe Journal of biological chemistry · 2020Article
- Two Isoforms of the Guanine Nucleotide Exchange Factor, Daple/CCDC88C Cooperate as Tumor Suppressors.Scientific reports · 2019Article
- A biochemical and genetic discovery pipeline identifies PLCδ4b as a nonreceptor activator of heterotrimeric G-proteins.The Journal of biological chemistry · 2018Article
- Specific inhibition of GPCR-independent G protein signaling by a rationally engineered protein.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- The Gαi-GIV binding interface is a druggable protein-protein interaction.Scientific reports · 2017Article
- Membrane Recruitment of the Non-receptor Protein GIV/Girdin (Gα-interacting, Vesicle-associated Protein/Girdin) Is Sufficient for Activating Heterotrimeric G Protein Signaling.The Journal of biological chemistry · 2016Article
- Biochemical, Biophysical and Cellular Techniques to Study the Guanine Nucleotide Exchange Factor, GIV/Girdin.Current protocols in chemical biology · 2016Article
- Article
- 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
- GIV/Girdin (Gα-interacting, Vesicle-associated Protein/Girdin) Creates a Positive Feedback Loop That Potentiates Outside-in Integrin Signaling in Cancer Cells.The Journal of biological chemistry · 2016Article
- The untapped potential of tyrosine-based G protein signaling.Pharmacological research · 2016Review
- Evolutionary Conservation of a GPCR-Independent Mechanism of Trimeric G Protein Activation.Molecular biology and evolution · 2016Article
- Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin.The Journal of cell biology · 2015Article
- Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration-proliferation dichotomy.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Heterotrimeric G proteins are critical signal-transducing molecules controlled by a complex network of regulators. GIV (a.k.a. Girdin) is a unique component of this network and a nonreceptor guanine nucleotide exchange factor (GEF) that functions via a signature motif. GIV's GEF motif is involved in the regulation of critical biological processes such as phosphoinositide 3 kinase (PI3K)-Akt signaling, actin cytoskeleton remodeling, cell migration, and cancer metastasis. Here we investigated how the GEF function of GIV affects the wiring of its signaling pathway to shape different biological responses. Using a structure-guided approach, we designed a battery of GIV mutants with different Gαi-binding and -activating properties and used it to dissect the specific impact of changes in GIV's GEF activity on several cellular responses. In vivo signaling assays revealed a threshold effect of GEF activity for the activation of Akt by GIV in different cell lines and by different stimuli. Akt signaling is minimal at low GEF activity and is sharply increased to reach a maximum above a threshold of GEF activity, suggesting that GIV is a critical signal amplifier and that activation of Akt is ultrasensitive to changes in GIV's GEF activity. A similar threshold dependence was observed for other biological functions promoted by GIV such as remodeling of the actin cytoskeleton and cell migration. This functional characterization of GIV's GEF motif provides insights into the molecular interactions between nonreceptor GEFs and G proteins and the mechanisms that govern this signal transduction pathway.
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