Complex effects of kinase localization revealed by compartment-specific regulation of protein kinase A activity

• Published in: eLife Vol. 11
• Main Authors: LaCroix, Rebecca, Lin, Benjamin, Kang, Tae-Yun, Levchenko, Andre
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 24-02-2022; eLife Sciences Publications, Ltd
• Subjects: Biochemistry and Chemical Biology; Biosensors; Catalytic subunits; Cell adhesion & migration; Cell cycle; Cell Membrane - metabolism; Cell migration; Cell Movement; Cell Polarity; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Enzymes; FRET; HeLa Cells; Humans; kinase activity; Kinases; Localization; microfluidics; Phenotypes; Phosphorylation; Physics of Living Systems; PKA; Protein kinase A; Protein Transport; Proteins; Regulation; Regulatory subunits; Signal Transduction; Sirolimus - metabolism; Tacrolimus Binding Proteins - metabolism; chemical biology; kinase activity; signal transduction; PKA; biochemistry; cell migration; FRET; none; microfluidics; physics of living systems
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/ELIFE.66869

Kinase activity in signaling networks frequently depends on regulatory subunits that can both inhibit activity by interacting with the catalytic subunits and target the kinase to distinct molecular partners and subcellular compartments. Here, using a new synthetic molecular interaction system, we show that translocation of a regulatory subunit of the protein kinase A (PKA-R) to the plasma membrane has a paradoxical effect on the membrane kinase activity. It can both enhance it at lower translocation levels, even in the absence of signaling inputs, and inhibit it at higher translocation levels, suggesting its role as a linker that can both couple and decouple signaling processes in a concentration-dependent manner. We further demonstrate that superposition of gradients of PKA-R abundance across single cells can control the directionality of cell migration, reversing it at high enough input levels. Thus, complex in vivo patterns of PKA-R localization can drive complex phenotypes, including cell migration.