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.
Original language | English |
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Pages (from-to) | 798-805 |
Number of pages | 8 |
Journal | Nature Structural and Molecular Biology |
Volume | 13 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2006 |
Externally published | Yes |
Bibliographical note
Funding Information:We thank D. Piston (Vanderbilt) for providing the mCerulean-C1 vector, W.Y. Langdon (University of Western Australia) for providing the CBL complementary DNA, D. Lowy (National Cancer Institute) for providing the SOS1 cDNA, P.P. Di Fiore (FIRC Institute for Molecular Oncology) for providing the GRB2 cDNA, A. Weiss (University of California at San Francisco) for providing the JCaM 2.5 Jurkat cell line and P. Schwartzberg and J. O’Shea for helpful discussions. This research was supported, in part, by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.
Funding
We thank D. Piston (Vanderbilt) for providing the mCerulean-C1 vector, W.Y. Langdon (University of Western Australia) for providing the CBL complementary DNA, D. Lowy (National Cancer Institute) for providing the SOS1 cDNA, P.P. Di Fiore (FIRC Institute for Molecular Oncology) for providing the GRB2 cDNA, A. Weiss (University of California at San Francisco) for providing the JCaM 2.5 Jurkat cell line and P. Schwartzberg and J. O’Shea for helpful discussions. This research was supported, in part, by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.
Funders | Funder number |
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National Institutes of Health | |
NIH Office of the Director | Z01OD010485 |
National Cancer Institute |