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

Jon C.D. Houtman, Hiroshi Yamaguchi, Mira Barda-Saad, Alex Braiman, Brent Bowden, Ettore Appella, Peter Schuck, Lawrence E. Samelson

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

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 languageEnglish
Pages (from-to)798-805
Number of pages8
JournalNature Structural and Molecular Biology
Volume13
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

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.

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