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Mol Cell. 2014 Jun 19;54(6):1034-41. doi: 10.1016/j.molcel.2014.05.002. Epub 2014 Jun 5.

Directed network wiring identifies a key protein interaction in embryonic stem cell differentiation.

Author information

1
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
2
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
3
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
4
Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: skoide@uchicago.edu.

Abstract

Cell signaling depends on dynamic protein-protein interaction (PPI) networks, often assembled through modular domains each interacting with multiple peptide motifs. This complexity raises a conceptual challenge, namely to define whether a particular cellular response requires assembly of the complete PPI network of interest or can be driven by a specific interaction. To address this issue, we designed variants of the Grb2 SH2 domain ("pY-clamps") whose specificity is highly biased toward a single phosphotyrosine (pY) motif among many potential pYXNX Grb2-binding sites. Surprisingly, directing Grb2 predominantly to a single pY site of the Ptpn11/Shp2 phosphatase, but not other sites tested, was sufficient for differentiation of the essential primitive endoderm lineage from embryonic stem cells. Our data suggest that discrete connections within complex PPI networks can underpin regulation of particular biological events. We propose that this directed wiring approach will be of general utility in functionally annotating specific PPIs.

PMID:
24910098
PMCID:
PMC4090938
DOI:
10.1016/j.molcel.2014.05.002
[Indexed for MEDLINE]
Free PMC Article

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