cAMP-dependent protein kinase A (PKA), ubiquitously expressed in mammalian cells, regulates a plethora of cellular processes through its ability to phosphorylate many protein substrates, including transcription factors, ion channels, apoptotic proteins, transporters, and metabolic enzymes. The PKA catalytic subunit has two phosphorylation sites, a well-studied site in the activation loop (Thr197) and another site in the C-terminal tail (Ser338) for which the role of phosphorylation is unknown. We show here, using in vitro studies and experiments with S49 lymphoma cells, that cis-autophosphorylation of Ser338 occurs cotranslationally, when PKA is associated with ribosomes and precedes posttranslational phosphorylation of the activation loop Thr197. Ser338 phoshorylation is not required for PKA activity or formation of the holoenzyme complex; however, it is critical for processing and maturation of PKA, and it is a prerequisite for phosphorylation of Thr197. After Thr197 and Ser338 are phosphorylated, both sites are remarkably resistant to phosphatases. Phosphatase resistance of the activation loop, a unique feature of both PKA and PKG, reflects the distinct way that signal transduction dynamics are controlled by cyclic nucleotide-dependent PKs.
Malik M. Keshwani; Christian Klammt; Sventja von Daake; Yuliang Ma; Alexandr P. Kornev; Senyon Choe; Paul A. Insel; Susan S. Taylor
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Influenza recurs seasonally in temperate regions of the world; however, our ability to predict the timing, duration, and magnitude of local seasonal outbreaks of influenza remains limited. Here we develop a framework for initializing real-time forecasts of seasonal influenza outbreaks, usin ... more
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