ArticleMolecular biology of the cell2014
Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin.
Article in Molecular biology of the cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 58 citations in OpenAlex.
- Small-molecule modulation of β-arrestins.Nature · 2026Article
- Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction.Human molecular genetics · 2025Article
- Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Growth factor-dependent phosphorylation of GαScience signaling · 2024Article
- Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif.The Journal of biological chemistry · 2024Review
- Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk.Cell reports · 2024Article
- 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
- Predictive data-driven modeling of C-terminal tyrosine function in the EGFR signaling network.Life science alliance · 2023Article
- 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
- Regulation of DNA damage response by trimeric G-proteins.iScience · 2023Article
- Role of G-Proteins and GPCRs in Cardiovascular Pathologies.Bioengineering (Basel, Switzerland) · 2023Review
- Identification of Six Diagnostic Biomarkers for Chronic Lymphocytic Leukemia Based on Machine Learning Algorithms.Journal of oncology · 2022Article
- Building unconventional G protein-coupled receptors, one block at a time.Trends in pharmacological sciences · 2021Article
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- 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
- Article
- Regulating cellular cyclic adenosine monophosphate: "Sources," "sinks," and now, "tunable valves".Wiley interdisciplinary reviews. Systems biology and medicine · 2020Review
- GIV/Girdin and Exo70 Collaboratively Regulate the Mammalian Polarized Exocytic Machinery.iScience · 2020Article
- The DISC1-Girdin complex - a missing link in signaling to the T cell cytoskeleton.Journal of cell science · 2020Article
- GIV•Kindlin Interaction Is Required for Kindlin-Mediated Integrin Recognition and Activation.iScience · 2020Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
A long-standing issue in the field of signal transduction is to understand the cross-talk between receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major and distinct signaling hubs that control eukaryotic cell behavior. Although stimulation of many RTKs leads to activation of trimeric G proteins, the molecular mechanisms behind this phenomenon remain elusive. We discovered a unifying mechanism that allows GIV/Girdin, a bona fide metastasis-related protein and a guanine-nucleotide exchange factor (GEF) for Gαi, to serve as a direct platform for multiple RTKs to activate Gαi proteins. Using a combination of homology modeling, protein-protein interaction, and kinase assays, we demonstrate that a stretch of ∼110 amino acids within GIV C-terminus displays structural plasticity that allows folding into a SH2-like domain in the presence of phosphotyrosine ligands. Using protein-protein interaction assays, we demonstrated that both SH2 and GEF domains of GIV are required for the formation of a ligand-activated ternary complex between GIV, Gαi, and growth factor receptors and for activation of Gαi after growth factor stimulation. Expression of a SH2-deficient GIV mutant (Arg 1745→Leu) that cannot bind RTKs impaired all previously demonstrated functions of GIV-Akt enhancement, actin remodeling, and cell migration. The mechanistic and structural insights gained here shed light on the long-standing questions surrounding RTK/G protein cross-talk, set a novel paradigm, and characterize a unique pharmacological target for uncoupling GIV-dependent signaling downstream of multiple oncogenic RTKs.
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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.