Substrate-dependent control of ERK phosphorylation can lead to oscillations

The extracellular signal-regulated kinase (ERK) controls cellular processes by phosphorylating multiple substrates. The ERK protein can use the same domains to interact with phosphatases, which dephosphorylate and deactivate ERK, and with substrates, which connect ERK to its downstream effects. As a consequence, substrates can compete with phosphatases and control the level of ERK phosphorylation. We propose that this effect can qualitatively change the dynamics of a network that controls ERK activation. On its own, this network can be bistable, but in a larger system, where ERK accelerates the degradation of a substrate competing with a phosphatase, this network can oscillate. Previous studies proposed that oscillatory ERK signaling requires a negative feedback in which active ERK reduces the rate at which it is phosphorylated by upstream kinase. We argue that oscillations can also emerge even when this rate is constant, due to substrate-dependent control of ERK phosphorylation.