Interaction domains of Sos1/Grb2 are finely tuned for cooperative control of embryonic stem cell fateFindlay GM, Smith MJ, Lanner F, Hsiung MS, Gish GD, Petsalakis E, Cockburn K, Kaneko T, Huang H, Bagshaw RD, Ketela T, Tucholska M, Taylor L, Bowtell DD, Moffat J, Ikura M, Li SS, Sidhu SS, Rossant J, Pawson T. Cell 2013 Feb 28; 152(5): 1008-1020 PMID: 23452850 doi: 10.1016/j.cell.2013.01.056.
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. [PubMed] [Publisher] [Lunenfeld Discovery Corner]
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