A two-component protein condensate of the EGFR cytoplasmic tail and Grb2 regulates Ras activation by SOS at the membrane

• DOI: 10.1073/pnas.2122531119
• Publication Date: 2022-05-04T19:55:42Z
• Authors: Chun-Wei Lin; Laura M. Nocka; Brittany L. Stinger; Joseph B. DeGrand...; L. J. Nugent Lew; Steven Alvarez; Henry T. Phan; Yasushi Kondo; John Kuriyan; Jay T. Groves
• Keywords: ErbB Receptors; 0303 health sciences; 03 medical and health sciences; Biological Sciences; Phosphorylation; Phosphotyrosine; GRB2 Adaptor Protein; Signal Transduction

Significance Two-dimensional condensates of proteins on the membrane surface, driven by tyrosine phosphorylation, are beginning to emerge as important players in signal transduction. This work describes discovery of a protein condensation phase transition of EGFR and Grb2 on membrane surfaces, which is poised to have a significant impact on how we understand EGFR signaling and misregulation in disease. EGFR condensation is mediated through a Grb2-Grb2 crosslinking element, which itself is regulatable through a specific phosphotyrosine site on Grb2. Furthermore, the EGFR condensate exerts significant control over the ability of SOS to activate Ras, thus implicating the EGFR condensate as a regulator of signal propagation from EGFR to Ras and the MAPK pathway.