Positive feedback between the T cell kinase Zap70 and its substrate LAT acts as a clustering-dependent signaling switch

Elliot Dine, Ellen H. Reed, Jared E. Toettcher

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number109280
JournalCell Reports
Volume35
Issue number12
DOIs
StatePublished - Jun 22 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • optogenetics
  • protein phase separation
  • T cell signaling
  • tyrosine kinases

Fingerprint

Dive into the research topics of 'Positive feedback between the T cell kinase Zap70 and its substrate LAT acts as a clustering-dependent signaling switch'. Together they form a unique fingerprint.

Cite this