title: Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fate.
abstract: 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.
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors: Greg M
authors: GM
authors: Findlay
authors: Matthew J
authors: MJ
authors: Smith
authors: Fredrik
authors: F
authors: Lanner
authors: Marilyn S
authors: MS
authors: Hsiung
authors: Gerald D
authors: GD
authors: Gish
authors: Evangelia
authors: E
authors: Petsalaki
authors: Katie
authors: K
authors: Cockburn
authors: Tomonori
authors: T
authors: Kaneko
authors: Haiming
authors: H
authors: Huang
authors: Richard D
authors: RD
authors: Bagshaw
authors: Troy
authors: T
authors: Ketela
authors: Monika
authors: M
authors: Tucholska
authors: Lorne
authors: L
authors: Taylor
authors: David D
authors: DD
authors: Bowtell
authors: Jason
authors: J
authors: Moffat
authors: Mitsuhiko
authors: M
authors: Ikura
authors: Shawn S C
authors: SS
authors: Li
authors: Sachdev S
authors: SS
authors: Sidhu
authors: Janet
authors: J
authors: Rossant
authors: Tony
authors: T
authors: Pawson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004707:Endoderm / Q000378:metabolism; D056890:Eukaryota / Q000235:genetics / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D020837:SOS1 Protein / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism
chemical_list: D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D020837:SOS1 Protein; D020663:ras Guanine Nucleotide Exchange Factors