ArticleProceedings of the National Academy of Sciences of the United States of America2020
Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 34 citations in OpenAlex.
- Regulation of Amino Acid Transporters by Cell Surface Receptors.Antioxidants (Basel, Switzerland) · 2026Review
- Phosphovariants of the canonical heterotrimeric Gα protein, GPA1, differentially affect G protein activity and Arabidopsis development.bioRxiv : the preprint server for biology · 2026Article
- Phosphorylation-activated G protein signaling stabilizes TCP14 and JAZ3 to repress JA signaling and enhance plant immunity.Molecular plant · 2025Article
- Ligand-dependent G protein dynamics underlying opioid signaling efficacy.bioRxiv : the preprint server for biology · 2025Article
- Blocking the isoflavone chemoreceptor inScience advances · 2025Article
- An Alternative Mode of GPCR Transactivation: Activation of GPCRs by Adhesion GPCRs.International journal of molecular sciences · 2025Review
- Evolution of phenotypic plasticity leads to tumor heterogeneity with implications for therapy.PLoS computational biology · 2024Article
- Growth factor-dependent phosphorylation of GαScience signaling · 2024Article
- Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities.International journal of molecular sciences · 2024Review
- 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
- A circuit for secretion-coupled cellular autonomy in multicellular eukaryotic cells.Molecular systems biology · 2023Article
- Distribution and the evolutionary history of G-protein components in plant and algal lineages.Plant physiology · 2022Article
- A Facile Platform to EngineerACS central science · 2022Article
- The Conformational Dynamics of Heterotrimeric G Proteins During GPCR-Mediated Activation.Sub-cellular biochemistry · 2022Review
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Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
The molecular mechanisms by which receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major signaling hubs in eukaryotes, independently relay signals across the plasma membrane have been extensively characterized. How these hubs cross-talk has been a long-standing question, but answers remain elusive. Using linear ion-trap mass spectrometry in combination with biochemical, cellular, and computational approaches, we unravel a mechanism of activation of heterotrimeric G proteins by RTKs and chart the key steps that mediate such activation. Upon growth factor stimulation, the guanine-nucleotide exchange modulator dissociates Gαi•βγ trimers, scaffolds monomeric Gαi with RTKs, and facilitates the phosphorylation on two tyrosines located within the interdomain cleft of Gαi. Phosphorylation triggers the activation of Gαi and inhibits second messengers (cAMP). Tumor-associated mutants reveal how constitutive activation of this pathway impacts cell's decision to "go" vs. "grow." These insights define a tyrosine-based G protein signaling paradigm and reveal its importance in eukaryotes.
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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.