Sos1/Grb2 domains - finely tuned to control ES cell fate
Written by Greg Findlay   
Friday, 22 March 2013

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

Findlay 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.



[Lunenfeld Discovery Corner] 


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