title: Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1.
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.
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jon C D
authors.initials: JC
authors.lastname: Houtman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Mira
authors.initials: M
authors.lastname: Barda-Saad
authors.forename: Alex
authors.initials: A
authors.lastname: Braiman
authors.forename: Brent
authors.initials: B
authors.lastname: Bowden
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Peter
authors.initials: P
authors.lastname: Schuck
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Samelson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020837:SOS1 Protein / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C110810:LAT protein, human; D008024:Ligands; D008565:Membrane Proteins; D010748:Phosphopeptides; D011948:Receptors, Antigen, T-Cell; D020837:SOS1 Protein; D011392:Proline