Research ArticleCell Biology

Kinetics of receptor tyrosine kinase activation define ERK signaling dynamics

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Science Signaling  18 Aug 2020:
Vol. 13, Issue 645, eaaz5267
DOI: 10.1126/scisignal.aaz5267

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Dynamics start at the receptor

Despite activating the same kinase effector, ERK, receptor tyrosine kinases (RTKs) trigger distinct biological responses. These responses stem from differences in the dynamics of ERK signaling, such that the transient ERK activation induced by EGF results in proliferation and the sustained ERK activation induced by NGF results in differentiation. Using chimeric and mutated receptors and inhibitors, Kiyatkin et al. found that switching EGFR activation from transient to sustained enabled sustained ERK activation and differentiation downstream of EGF stimulation. These findings contrast with the currently held notion that ERK activation dynamics depend largely on the topology of the networks connecting different RTKs to ERK. The authors propose that redirecting signal dynamics may be a more fruitful and effective approach than current therapeutic strategies to completely block RTK or effector activation in pathological situations.

Abstract

In responses to activation of receptor tyrosine kinases (RTKs), crucial cell fate decisions depend on the duration and dynamics of ERK signaling. In PC12 cells, epidermal growth factor (EGF) induces transient ERK activation that leads to cell proliferation, whereas nerve growth factor (NGF) promotes sustained ERK activation and cell differentiation. These differences have typically been assumed to reflect distinct feedback mechanisms in the Raf-MEK-ERK signaling network, with the receptors themselves acting as simple upstream inputs. We failed to confirm the expected differences in feedback type when investigating transient versus sustained signaling downstream of the EGF receptor (EGFR) and NGF receptor (TrkA). Instead, we found that ERK signaling faithfully followed RTK dynamics when receptor signaling was modulated in different ways. EGFR activation kinetics, and consequently ERK signaling dynamics, were switched from transient to sustained when receptor internalization was inhibited with drugs or mutations, or when cells expressed a chimeric receptor likely to have impaired dimerization. In addition, EGFR and ERK signaling both became more sustained when substoichiometric levels of erlotinib were added to reduce duration of EGFR kinase activation. Our results argue that RTK activation kinetics play a crucial role in determining MAP kinase cascade signaling dynamics and cell fate decisions, and that signaling outcome can be modified by activating a given RTK in different ways.

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