Bistability in the JNK cascade

Abstract

Background: Important signaling properties, like adaptation, oscillations, and bistability, can emerge at the level of relatively simple systems of signaling proteins. Here, we have examined the quantitative properties of one well-studied signaling system, the JNK cascade. We experimentally assessed the response of JNK to a physiological stimulus (progesterone) and a pathological stress (hyperosmolar sorbitol) in Xenopus laevis oocytes, a cell type that is well-suited to the quantitative analysis of cell signaling. Our aim was to determine whether JNK responses are graded (Michaelian) in character; ultrasensitive in character, resembling the responses of cooperative enzymes; or bistable and all-or-none in character.

Results: The responses of JNK to both progesterone and sorbitol were found to be essentially all-or-none. Individual oocytes had either very high or very low JNK activities, with few oocytes possessing intermediate levels of JNK activity. Moreover, JNK activation was autocatalytic, indicating that the JNK cascade is either embedded in or downstream of a positive feedback loop. JNK also exhibited hysteresis, a form of biochemical memory, in its response to sorbitol. These findings indicate that the JNK cascade is part of a bistable signaling system in oocytes.

Conclusions: In Xenopus oocytes, JNK responds to physiological and pathological stimuli in an all-or-none manner. The JNK response shows all the hallmarks of a bistable response, including strong positive feedback and hysteresis. Bistability is a recurring theme in the biochemistry of oocyte maturation and early embryogenesis; the Mos/MEK/p42 MAPK cascade also exhibits bistable responses, and the Cdc2/cyclin B system is hypothesized to be bistable as well. However, the mechanisms underpinning the positive feedback and bistability in the three cases are different, suggesting that evolution has repeatedly converged upon bistability as a way of producing digital responses.