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

Nat Immunol. 2017 Jan;18(1):86-95. doi: 10.1038/ni.3631. Epub 2016 Nov 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Activity Cycles*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antigens / immunology
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Phosphoproteins / metabolism
  • Receptor Cross-Talk
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Antigens
  • Lat protein, mouse
  • Membrane Proteins
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • ZAP-70 Protein-Tyrosine Kinase