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J Biol Chem, Vol. 273, Issue 33, 21194-21202, August 14, 1998
From the Departments of CD28 provides a costimulatory signal that results
in optimal activation of T cells. The signal transduction pathways
necessary for CD28-mediated costimulation are presently unknown.
Engagement of CD28 leads to its tyrosine phosphorylation and subsequent
binding to Src homology 2 (SH2)-containing proteins including the p85 subunit of phosphatidylinositol 3'-kinase (PI3K); however, the contribution of PI3K to CD28-dependent costimulation
remains controversial. Here we show that CD28 is capable of binding the
Src homology 3 (SH3) domains of several proteins, including Grb2. The
interaction between Grb2 and CD28 is mediated by the binding of
Grb2-SH3 domains to the C-terminal diproline motif present in the
cytoplasmic domain of CD28. While the affinity of the C-terminal SH3
domain of Grb2 for CD28 is greater than that of the N-terminal SH3
domain, optimal binding requires both SH3 domains. Ligation of CD28,
but not tyrosine-phosphorylation, is required for the SH3-mediated
binding of Grb2 to CD28. We propose a model whereby the association of
Grb2 with CD28 occurs via an inducible SH3-mediated interaction and
leads to the recruitment of tyrosine-phosphorylated proteins such as
p52shc bound to the SH2 domain of Grb2. The inducible
interaction of Grb2 to the C-terminal region of CD28 may form the basis
for PI3K-independent signaling through CD28.
Grb2 Forms an Inducible Protein Complex with CD28 through a Src
Homology 3 Domain-Proline Interaction
§ and§¶
Immunology and
¶ Medicine, University of Toronto, Toronto, Ontario M5S
1A2, Canada and § Ontario Cancer Institute/Princess Margaret Hospital,
Toronto, Ontario M5G 2M9, Canada
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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