Immunoreceptor tyrosine-based activation motifs ITAMs

In B lymphocytes, coupling of the antigen receptors to Erk MAPkinase is protein tyrosine kinase (PTK)-dependent (Pao et al, 1997). Following ligation of the BCR (Fig. 19.2) the PTK, Lyn, tyrosine phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) on the accessory transducing molecules Ig-a and Ig-(3, leading to the recruitment... 

Ig-a-Ig-P heterodimers. The intracellular domains of each of the Ig-a and Ig-[3 chains include an immunoreceptor tyrosine-based activation motif (ITAM). 

Associated with each membrane-linked IgM molecule are two molecules of a heterodimeric membrane protein called Ig-a-Ig-p (see Figure 33.21). Examination of the amino acid sequences of Ig-a and Ig-P is highly instructive. The amino terminus of each protein lies outside the cell and corresponds to a single immunoglobulin, and the carboxyl terminus, which lies inside the cell, includes a sequence of 18 amino acids called an immunoreceptor tyrosine-based activation motif (ITAM see Figure 33.21). As its name suggests, each ITAM includes key tyrosine residues, which are subject to phosphorylation by particular protein kinases present in immune-system cells. 

The protein p56 lymphoid T-cell tyrosine kinase (Lck) is predominantly expressed in T lymphocytes where it plays a critical role in T-cell-mediated immune response. Lck participates in phosphotyrosine-dependent protein-protein interactions through its modular binding unit, the Src homology-2 (SH2) domain. SH2 domains are noncatalytic modules of about 100 amino acid residues that play important roles in intracellular signal transduction and represent potential targets for pharmacological intervention. Failure of the p5 6 Lck S H 2 domain to bind to immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 hampers the T-cell receptor (TCR) proximal activation process and suppresses the downstream T-cell activation signaling cascades [143]. Small compounds that would be able to block Lck SH2 domain-dependent protein-protein interactions could find therapeutic utility as immunosuppressants and in the treatment of T-cell leukemias, lymphomas, and autoimmune diseases such as rheumatoid arthritis. 

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