Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1

Authors:
Houtman JC, Yamaguchi H, Barda-Saad M, Braiman A, Bowden B, Appella E, Schuck P, Samelson LE
In:
Source: Nat Struct Mol Biol
Publication Date: (2006)
Issue: 13(9): 798-805
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
Jurkat
Species: human
Tissue Origin: blood
Platform:
Nucleofector® I/II/2b
Abstract
Receptor oligomerization is vital for activating intracellular signaling, in part by initiating events that recruit effector and adaptor proteins to sites of active signaling. Whether these distal molecules themselves oligomerize is not well appreciated. In this study, we examined the molecular interactions of the adaptor protein GRB2. In T cells, the SH2 domain of GRB2 binds phosphorylated tyrosines on the adaptor protein LAT and the GRB2 SH3 domains associate with the proline-rich regions of SOS1 and CBL. Using biochemical and biophysical techniques in conjunction with confocal microscopy, we observed that the simultaneous association of GRB2, via its SH2 and SH3 domains, with multivalent ligands led to the oligomerization of these ligands, which affected signaling. These data suggest that multipoint binding of distal adaptor proteins mediates the formation of oligomeric signaling clusters vital for intracellular signaling.