Spatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network
| Autor: | Mark von Zastrow, Grace E. Peng, Bo Huang, Veronica Pessino |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cytoplasm
Endosome Green Fluorescent Proteins Endosomes Article 03 medical and health sciences Genes Reporter Catalytic Domain Metastability Cyclic AMP medicine Transcriptional regulation Animals Humans RNA Small Interfering Luciferases Receptor Protein kinase A Molecular Biology Close contact Dynamin I 030304 developmental biology Cell Nucleus 0303 health sciences Chemistry 030302 biochemistry & molecular biology Cell Biology Cyclic AMP-Dependent Protein Kinases Rats Protein Subunits HEK293 Cells medicine.anatomical_structure Gene Expression Regulation Clathrin Heavy Chains Biophysics Receptors Adrenergic beta-2 Holoenzymes Nucleus Protein Binding Signal Transduction |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | G-protein-coupled receptor-regulated cAMP production from endosomes can specify signaling to the nucleus by moving the source of cAMP without changing its overall amount. How this is possible remains unknown because cAMP gradients dissipate over the nanoscale, whereas endosomes typically localize micrometers from the nucleus. We show that the key location-dependent step for endosome-encoded transcriptional control is nuclear entry of cAMP-dependent protein kinase (PKA) catalytic subunits. These are sourced from punctate accumulations of PKA holoenzyme that are densely distributed in the cytoplasm and titrated by global cAMP into a discrete metastable state, in which catalytic subunits are bound but dynamically exchange. Mobile endosomes containing activated receptors collide with the metastable PKA puncta and pause in close contact. We propose that these properties enable cytoplasmic PKA to act collectively like a semiconductor, converting nanoscale cAMP gradients generated from endosomes into microscale elevations of free catalytic subunits to direct downstream signaling. |
| Databáze: | OpenAIRE |
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