Abstract
In both physiological and cell culture systems, EGF-stimulated ERK activity occurs in discrete pulses within individual cells. Many feedback loops are present in the EGF receptor (EGFR)-ERK network, but the mechanisms driving pulsatile ERK kinetics are unknown. Here, we find that in cells that respond to EGF with frequency-modulated pulsatile ERK activity, stimulation through a heterologous TrkA receptor system results in non-pulsatile, amplitude-modulated activation of ERK. We further dissect the kinetics of pulse activity using a combination of FRET- and translocation-based reporters and find that EGFR activity is required to maintain ERK activity throughout the 10-20-minute lifetime of pulses. Together, these dataindicatethat feedbacks operating within the core Ras-Raf-MEK-ERK cascade are insufficient to drive discrete pulses of ERK activity and instead implicate mechanisms acting at the level of EGFR.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 24784-24792 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 290 |
| Issue number | 41 |
| DOIs | |
| State | Published - Oct 9 2015 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Receptor level mechanisms are required for epidermal growth factor (EGF)-stimulated extracellular signal-regulated kinase (ERK) activity pulses. / Sparta, Breanne; Pargett, Michael; Minguet, Marta; Distor, Kevin; Bell, George; Albeck, John.
In: Journal of Biological Chemistry, Vol. 290, No. 41, 09.10.2015, p. 24784-24792.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Receptor level mechanisms are required for epidermal growth factor (EGF)-stimulated extracellular signal-regulated kinase (ERK) activity pulses
AU - Sparta, Breanne
AU - Pargett, Michael
AU - Minguet, Marta
AU - Distor, Kevin
AU - Bell, George
AU - Albeck, John
PY - 2015/10/9
Y1 - 2015/10/9
N2 - In both physiological and cell culture systems, EGF-stimulated ERK activity occurs in discrete pulses within individual cells. Many feedback loops are present in the EGF receptor (EGFR)-ERK network, but the mechanisms driving pulsatile ERK kinetics are unknown. Here, we find that in cells that respond to EGF with frequency-modulated pulsatile ERK activity, stimulation through a heterologous TrkA receptor system results in non-pulsatile, amplitude-modulated activation of ERK. We further dissect the kinetics of pulse activity using a combination of FRET- and translocation-based reporters and find that EGFR activity is required to maintain ERK activity throughout the 10-20-minute lifetime of pulses. Together, these dataindicatethat feedbacks operating within the core Ras-Raf-MEK-ERK cascade are insufficient to drive discrete pulses of ERK activity and instead implicate mechanisms acting at the level of EGFR.
AB - In both physiological and cell culture systems, EGF-stimulated ERK activity occurs in discrete pulses within individual cells. Many feedback loops are present in the EGF receptor (EGFR)-ERK network, but the mechanisms driving pulsatile ERK kinetics are unknown. Here, we find that in cells that respond to EGF with frequency-modulated pulsatile ERK activity, stimulation through a heterologous TrkA receptor system results in non-pulsatile, amplitude-modulated activation of ERK. We further dissect the kinetics of pulse activity using a combination of FRET- and translocation-based reporters and find that EGFR activity is required to maintain ERK activity throughout the 10-20-minute lifetime of pulses. Together, these dataindicatethat feedbacks operating within the core Ras-Raf-MEK-ERK cascade are insufficient to drive discrete pulses of ERK activity and instead implicate mechanisms acting at the level of EGFR.
UR - http://www.scopus.com/inward/record.url?scp=84943736810&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943736810&partnerID=8YFLogxK
U2 - 10.1074/jbc.M115.662247
DO - 10.1074/jbc.M115.662247
M3 - Article
C2 - 26304118
AN - SCOPUS:84943736810
VL - 290
SP - 24784
EP - 24792
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 41
ER -