Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate

Greg M. Findlay (Lead / Corresponding author), Matthew J. Smith, Fredrik Lanner, Marilyn S. Hsiung, Gerald D. Gish, Evangelia Petsalaki, Katie Cockburn, Tomonori Kaneko, Haiming Huang, Richard D. Bagshaw, Troy Ketela, Monika Tucholska, Lorne Taylor, David D. Bowtell, Jason Moffat, Mitshuhiko Ikura, Shawn S.C. Li, Sachdev S. Sidhu, Janet Rossant, Tony Pawson

    Research output: Contribution to journalArticlepeer-review

    50 Citations (Scopus)


    Metazoan evolution involves increasing protein domain complexity, but how this relates to control of biological decisions remains uncertain. The Ras guanine nucleotide exchange factor (RasGEF) Sos1 and its adaptor Grb2 are multidomain proteins that couple fibroblast growth factor (FGF) signaling to activation of the Ras-Erk pathway during mammalian development and drive embryonic stem cells toward the primitive endoderm (PrE) lineage. We show that the ability of Sos1/Grb2 to appropriately regulate pluripotency and differentiation factors and to initiate PrE development requires collective binding of multiple Sos1/Grb2 domains to their protein and phospholipid ligands. This provides a cooperative system that only allows lineage commitment when all ligand-binding domains are occupied. Furthermore, our results indicate that the interaction domains of Sos1 and Grb2 have evolved so as to bind ligands not with maximal strength but with specificities and affinities that maintain cooperativity. This optimized system ensures that PrE lineage commitment occurs in a timely and selective manner during embryogenesis.
    Original languageEnglish
    Pages (from-to)1008-1020
    Number of pages13
    Issue number5
    Publication statusPublished - 28 Feb 2013


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