@article{4167,
  keywords = {Animals, Mice, Humans, Models, Biological, Signal Transduction, Substrate Specificity, Membrane Proteins, Phosphorylation, Feedback, Physiological, Enzyme Activation, Light, Cluster Analysis, NIH 3T3 Cells, Optogenetics, Protein Multimerization, Calcium Signaling, Adaptor Proteins, Signal Transducing, Jurkat Cells, ZAP-70 Protein-Tyrosine Kinase},
  author = {Elliot Dine and Ellen Reed and Jared Toettcher},
  title = {Positive feedback between the T~cell kinase Zap70 and its substrate LAT acts as a clustering-dependent signaling switch.},
  abstract = { <p>Protein clustering is pervasive in cell signaling, yet how signaling from higher-order assemblies differs from simpler forms of molecular organization is still poorly understood. We present an optogenetic approach to switch between oligomers and heterodimers with a single point mutation. We apply this system to study signaling from the kinase Zap70 and its substrate linker for activation of T~cells (LAT), proteins that normally form membrane-localized condensates during T~cell activation. We find that fibroblasts expressing synthetic Zap70:LAT clusters activate downstream signaling, whereas one-to-one heterodimers do not. We provide evidence that clusters harbor a positive feedback loop among Zap70, LAT, and Src-family kinases that binds phosphorylated LAT and further activates Zap70. Finally, we extend our optogenetic approach to the native T~cell signaling context, where light-induced LAT clustering is sufficient to drive a calcium response. Our study reveals a specific signaling function for protein clusters and identifies a biochemical circuit that robustly senses protein oligomerization state.</p> },
  year = {2021},
  journal = {Cell Rep},
  volume = {35},
  pages = {109280},
  month = {2021 Jun 22},
  issn = {2211-1247},
  doi = {10.1016/j.celrep.2021.109280},
  language = {eng},
}