Skip to content
DraconiticResearch
Search Sources API
197,357 studies31 sourcesUpdated 25 min ago
Peer-reviewedCC BYPLOS One

Grb2 phosphorylation antagonizes EGFR-driven ras activation by interfering with condensate assembly

  • Henry T Phan1
  • Chun-Wei Lin2
  • Brittany L Stinger1
  • Joseph B DeGrandchamp1
  • L J Nugent Lew1
  • Serena J Huang1
  • Jay T Groves1,3,4
4 affiliations
  1. 1Department of Chemistry, University of California Berkeley, Berkeley, California, United States of America.
  2. 2Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan.
  3. 3California Institute for Quantitative Biosciences, University of California, Berkeley, California, United States of America.
  4. 4Divisions of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
Read full textPDFDOICite

Abstract

Upon ligand binding, the kinase domain of EGFR phosphorylates multiple tyrosine residues on the receptor cytoplasmic tail through a trans-autophosphorylation process. Phosphotyrosine sites on activated receptors recruit Grb2, which further recruits SOS to initiate downstream signaling by activating Ras. Multivalent binding between SOS and Grb2, as well as direct Grb2:Grb2 interactions, contribute to formation of a protein condensate of activated EGFR. The condensed state of EGFR facilitates autoinhibition release in SOS and exerts regulatory control over signal propagation from activated EGFR to Ras. While kinase activity of EGFR is an essential driver of this signaling process, phosphorylation at residue Y160 on Grb2 blocks Grb2:Grb2 binding and can interfere with EGFR condensation. Here, using a reconstituted system, we examine how titrating kinase activity in the EGFR system can both promote and inhibit signal output to Ras. The results reveal how effects of tyrosine kinase inhibition can, under some circumstances, promote Ras activation by inhibiting negative feedback through Grb2 phosphorylation and disruption of a Grb2 SH2/SH3 dimer interface.

Related

  1. Site-comprehensive phosphorylation dismantles a disordered interaction hub to drive Cdc25C activation
    Tan Tan, Chuanfen Wu, Ruoning Wang +3
    iSciencePeer-reviewedCC BY 4.0Molecular biology & gene regulationCell biologyCrossrefCell Press
  2. HS‐AFM Reveals Hierarchical RNA Folding Driving Condensate Assembly and Material States
    S. M. Neaz Mahmud, Kenichi Umeda, Tamoghna Das +3
    Small (Weinheim an Der Bergstrasse, Germany)Peer-reviewedCC BY-NC-ND 4.0Full textMolecular biology & gene regulationPMC
  3. LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation
    He Ren, Hyun-Ro Lee, Yannick A. D. Omar +7
    Proceedings of the National Academy of Sciences of the United States of AmericaPeer-reviewedCC BY 4.0Full text1 citedMolecular biology & gene regulationPMC
  4. Asymmetric assembly underlies activation mechanism of neuronal GIRK1/2 channels
    T. Kawano, L. Wang, K. W. Chan +15
    bioRxivPreprintCC BY-NC-NDFull textBiophysicsbioRxiv
  5. Structural basis of assembly-dependent activation of the MAD3–MAD4 nuclease in the Pseudomonas aeruginosa MADS defense system
    Jin Zhang, Zengru Li, Le Ye +3
    Nucleic Acids ResearchPeer-reviewedCC BY-NC 4.0Full textMolecular biology & gene regulationCrossref

Cite

BibTeXRIS
BibTeX
@article{phan2026grb2,
  title = {{Grb2 phosphorylation antagonizes EGFR-driven ras activation by interfering with condensate assembly}},
  author = {Henry T Phan and Chun-Wei Lin and Brittany L Stinger and Joseph B DeGrandchamp and L J Nugent Lew and Serena J Huang and Jay T Groves},
  journal = {PLOS One},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pone.0361303},
  url = {https://doi.org/10.1371/journal.pone.0361303},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Grb2 phosphorylation antagonizes EGFR-driven ras activation by interfering with condensate assembly
AU  - Henry T Phan
AU  - Chun-Wei Lin
AU  - Brittany L Stinger
AU  - Joseph B DeGrandchamp
AU  - L J Nugent Lew
AU  - Serena J Huang
AU  - Jay T Groves
PY  - 2026
DA  - 2026/10/26
JO  - PLOS One
DO  - 10.1371/journal.pone.0361303
UR  - https://doi.org/10.1371/journal.pone.0361303
AB  - Upon ligand binding, the kinase domain of EGFR phosphorylates multiple tyrosine residues on the receptor cytoplasmic tail through a trans-autophosphorylation process. Phosphotyrosine sites on activated receptors recruit Grb2, which further recruits SOS to initiate downstream signaling by activating Ras. Multivalent binding between SOS and Grb2, as well as direct Grb2:Grb2 interactions, contribute to formation of a protein condensate of activated EGFR. The condensed state of EGFR facilitates autoinhibition release in SOS and exerts regulatory control over signal propagation from activated EGFR to Ras. While kinase activity of EGFR is an essential driver of this signaling process, phosphorylation at residue Y160 on Grb2 blocks Grb2:Grb2 binding and can interfere with EGFR condensation. Here, using a reconstituted system, we examine how titrating kinase activity in the EGFR system can both promote and inhibit signal output to Ras. The results reveal how effects of tyrosine kinase inhibition can, under some circumstances, promote Ras activation by inhibiting negative feedback through Grb2 phosphorylation and disruption of a Grb2 SH2/SH3 dimer interface.
SN  - 1932-6203
ER  -