ArticleCell communication and signaling : CCS2023
Crk proteins activate the Rap1 guanine nucleotide exchange factor C3G by segregated adaptor-dependent and -independent mechanisms.
Article in Cell communication and signaling : CCS, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 12 citations in OpenAlex.
- Insights into protein synthesis dynamics of gilts from the same genetic background and age differing in protein deposition.Scientific reports · 2026Article
- Rapgef1 paralog-mediated regulation of Wnt/β-catenin signaling orchestrates early embryo tissue patterning and morphogenesis.Cell communication and signaling : CCS · 2026Article
- RasGRP3 Promotes RAP1B Activity to Inhibit Endothelial Inflammation and Alleviate Atherosclerosis in High-Fat Diet-Fed ApoEInflammation · 2026Article
- Emerging Potential of Ras-proximate-1 (Rap1) in Mediating Neurodegenerative Diseases.Current neuropharmacology · 2026Review
- C3G deregulation uncovers a dual role in B-cell lymphoma: tumor suppression and enhanced metastasis via Rap1 and Rac2 signaling.Cell communication and signaling : CCS · 2025Article
- Regulation of Rho guanine nucleotide exchange factor 3 by phosphorylation in the PH domain.iScience · 2025Article
- Development and tissue specific expression of RAPGEF1 (C3G) transcripts having exons encoding disordered segments with predicted regulatory function.Molecular biology reports · 2024Article
- Identification of hub genes and transcription factors in patients with primary gout complicated with atherosclerosis.Scientific reports · 2024Article
- Platelet C3G: a key player in vesicle exocytosis, spreading and clot retraction.Cellular and molecular life sciences : CMLS · 2024Article
- Cepharanthine inhibits migration, invasion, and EMT of bladder cancer cells by activating the Rap1 signaling pathway in vitro.American journal of translational research · 2024Article
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11 authors at 4 institutions in 4 countries.
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Abstract
backgroundC3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood.
methodsWe combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors.
resultsCrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G.
conclusionOur study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight control of C3G activation. Additionally, the simultaneous SH2 and SH3N interaction of CrkL with C3G, required for the activation, reveals a novel adaptor-independent function of Crk proteins relevant to understanding their role in physiological signaling and their deregulation in diseases. Video abstract.
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