Coordinated Pulses of mRNA and of Protein Translation or Degradation Produce EGF-Induced Protein Bursts

Abstract

Protein responses to extracellular cues are governed by gene transcription, mRNA degradation and translation, and protein degradation. In order to understand how these time-dependent processes cooperate to generate dynamic responses, we analyzed the response of human mammary cells to the epidermal growth factor (EGF). Integrating time-dependent transcript and protein data into a mathematical model, we inferred for several proteins their pre-and post-stimulus translation and degradation coefficients and found that they exhibit complex, time-dependent variation. Specifically, we identified strategies of protein production and degradation acting in concert to generate rapid, transient protein bursts in response to EGF. Remarkably, for some proteins, for which the response necessitates rapidly decreased abundance, cells exhibit a transient increase in the corresponding degradation coefficient. Our model and analysis allow inference of the kinetics of mRNA translation and protein degradation, without perturbing cells, and open a way to understanding the fundamental processes governing time-dependent protein abundance profiles.

Measuring mRNA translation in neuronal processes and somata by tRNA-FRET

“…We then measured the patterns of neuronal mRNA translation over time following stimulation.Chemical activation of LTP in vitro revealed a pulsatile pattern of global mRNA translation up-regulation that persisted at least six hours post activation. This observation is supported by numerous findings from both in vitro(76) and in vivo studies(69)(70)(71)(72)(73)(74)(75), as well as by the observation of biphasic activation of mRNA translation regulator mTOR(68), that suggest dependency of neuronal processes such as late-phase LTP (L-LTP) and long term memory consolidation upon two or more waves of de novo protein synthesis. Conceivably, our results may also be supported 24 by a similar pattern of up-regulation of transcription of Arc mRNA, an immediate early gene (IEG) known to be activated in response to LTP(42,43), which is synthesized in waves approximately two hours apart and transported into dendrites (25).…”

Molecularly Distinct Clathrin-Coated Pits Differentially Impact EGFR Fate and Signaling

“…Ultimately, EGFR activation results in the activation of transcriptional programs involving immediate-early genes (IEGs; at 30–45 min) (i.e., the transcription factors FOS , EGR1 , JUN , and JUNB ) and delayed early genes (DEGs; at 1–2 h), including DUSP5 and AREG ( Brankatschk et al., 2012 , Avraham and Yarden, 2011 , Avraham et al., 2010 ). The kinetics of these events are thought to define the specificity of the downstream transcriptional program ( Golan-Lavi et al., 2017 ), determining the final cellular outcome.…”

A Proteomics Approach to Profiling the Temporal Translational Response to Stress and Growth

“…Cellular response to perturbation often leads to a change in cell state, accompanied by dynamic alterations in protein synthesis and degradation that ultimately result in changes in protein expression levels ( Golan-Lavi et al., 2017 ). Measuring changes in mRNA abundance is commonly used to estimate changes in protein expression; however, relative mRNA abundance has been shown to be an incomplete predictor of protein synthesis and abundance ( Schwanhäusser et al., 2011 , Jovanovic et al., 2015 ) because translation is a highly regulated process that can be modulated by signaling pathways ( Rowlands et al., 1988 , Feng et al., 1992 , Chen and London, 1995 , Berlanga et al., 1999 , Gingras et al., 2001 , Novoa et al., 2003 ), RNA structural elements ( Filbin and Kieft, 2009 ), and tRNA isoacceptor availability ( Chan et al., 2010 , Chan et al., 2012 , Chionh et al., 2016 ).…”