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Lad, an Adapter Protein Interacting with the SH2 Domain of p56^lck, Is Required for T Cell Activation^{1 ,2}

Young Bong Choi^*,, Chan Ki Kim^* and Yungdae Yun^3,*,

^* Signal Transduction Laboratory Mogam Biotechnology Research Institute, Koosungmyon, Yonginsi, Kyunggido, Korea; and Department of Molecular Life Science and Center for Cell Signaling Research, Ewha Women’s University, Seodaemungu, Daehyundong 11-1, Seoul, 120-750, Korea.

T cell-specific Src family tyrosine kinase, p56^lck, plays crucial roles in T cell differentiation, activation, and proliferation. These multiple functions of p56^lck are believed to be conducted through the protein-protein interactions with various cellular signaling proteins. To clarify the mechanisms through which p56^lck contributes to T cell signaling, we identified the proteins binding to the Src homology 2 (SH2) domain of p56^lck through a tyrosine phosphorylation-dependent yeast two-hybrid screening. Subsequent characterization of positive clones revealed the presence of a protein of 366 aa named Lad (Lck-associated adapter protein), which is a potential murine homologue of previously reported TSAd, a T cell-specific adapter protein. Lad contains several protein-protein interaction domains including a zinc-finger motif, an SH2 domain, a proline-rich SH3 binding motif, and several phosphotyrosine sites. Furthermore, Lad was tyrosine phosphorylated and associated with p56^lck in vivo and redistributed from cytoplasm to the plasma membrane in a T cell activation-dependent manner. Moreover in T cells, IL-2 promoter activity was enhanced upon coexpression of Lad but was inhibited by the coexpression of antisense Lad RNA. These characteristics of Lad suggest that Lad play an essential role as an adapter protein in p56^lck-mediated T cell signaling.

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