Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells

Sho Yamasaki, Keigo Nishida, Machie Sakuma, Donna Berry, C. Jane McGlade, Toshio Hirano, Takashi Saito

    Research output: Contribution to journalArticle

    49 Citations (Scopus)

    Abstract

    A docking protein, Gab2, is recruited to the vicinity of the TCR complex and inhibits downstream signaling by interaction with negative regulators. However, the molecular mechanisms of this recruitment remain unclear. We have found that Gab2 associates with LAT upon TCR stimulation and that LAT is essential for Gab2 phosphorylation. By analysis of several Gab2 mutants, the c-Met binding domain (MBD) of Gab2 was found to be both necessary and sufficient for stimulation-induced LAT binding. Within the MBD domain, a novel Grb2 SH3 binding motif, PXXXR, is critical for constitutive association with Gads/Grb2. Through this association, Gab2 is recruited to the lipid raft after TCR ligation and exerts inhibitory function. The in vivo significance of this association is illustrated by the fact that T-cell responses are impaired in transgenic mice expressing wild-type Gab2 but not in mice expressing mutant Gab2 lacking the motif. Furthermore, T cells from Gab2-deficient mice showed enhanced proliferative responses upon TCR stimulation. These results indicate that Gads/Grb2-mediated LAT association is critical for the inhibitory function of Gab2, implying that Gab2 induced in stimulated T cells may exert an efficient negative feedback loop by recruiting inhibitory molecules to the lipid raft and competing with SLP-76 through Gads binding.

    Original languageEnglish
    Pages (from-to)2515-2529
    Number of pages15
    JournalMolecular and cellular biology
    Volume23
    Issue number7
    DOIs
    Publication statusPublished - Apr 2003

    All Science Journal Classification (ASJC) codes

    • Molecular Biology
    • Cell Biology

    Fingerprint Dive into the research topics of 'Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells'. Together they form a unique fingerprint.

  • Cite this

    Yamasaki, S., Nishida, K., Sakuma, M., Berry, D., McGlade, C. J., Hirano, T., & Saito, T. (2003). Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells. Molecular and cellular biology, 23(7), 2515-2529. https://doi.org/10.1128/MCB.23.7.2515-2529.2003