A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli

• Published in: Nature immunology Vol. 18; no. 1; pp. 86 - 95
• Main Authors: Katz, Zachary B, Novotná, Lucie, Blount, Amy, Lillemeier, Björn F
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2017; Nature Publishing Group
• Subjects: 631/250/516; 631/45/275; Activity Cycles; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antigens - immunology; Biomedicine; HEK293 Cells; Humans; Immunology; Infectious Diseases; Jurkat Cells; Lymphocyte Activation; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Phosphoproteins - metabolism; Phosphotransferases; Physiological aspects; Receptor Cross-Talk; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Signal Transduction - immunology; T cells; T-Lymphocytes - immunology; ZAP-70 Protein-Tyrosine Kinase - metabolism; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3631

Lillemeier and colleagues describe a cycle of recruitment, activation and release of Zap70 kinase at phosphorylated T cell antigen receptors. According to this model, the receptor acts as a ‘catalytic unit’ that amplifies antigenic stimuli.
Cell-surface-receptor pathways amplify weak, rare and local stimuli to induce cellular responses. This task is accomplished despite signaling components that segregate into nanometer-scale membrane domains. Here we describe a 'catch-and-release' mechanism that amplified and dispersed stimuli by releasing activated kinases from receptors lacking intrinsic catalytic activity. Specifically, we discovered a cycle of recruitment, activation and release for Zap70 kinases at phosphorylated T cell antigen receptors (TCRs). This turned the TCR into a 'catalytic unit' that amplified antigenic stimuli. Zap70 released from the TCR remained at the membrane, translocated, and phosphorylated spatially distinct substrates. The mechanisms described here are based on widely used protein domains and post-translational modifications; therefore, many membrane-associated pathways might employ similar mechanisms for signal amplification and dispersion.