The JNK Cascade as a Biochemical Switch in Mammalian Cells

Abstract

JNK proteins are ubiquitously expressed, evolutionarily conserved MAP kinases that are involved in stress responses. Recently, it was shown that the JNK cascade in Xenopus oocytes exhibits sustained, all-or-none responses to graded, transient stimuli. Here, we have examined the character of the JNK cascade's response in mammalian cells. The steady-state responses of JNK to sorbitol and anisomycin were found to be highly ultrasensitive in HeLa cells, HEK 293 cells, and Jurkat T cells. The JNK responses were also reversible, not sustained, as was the case in oocytes. Jurkat cells activated their JNK in response to phorbol myristate acetate (PMA), and the response of the entire population of Jurkat cells was graded. However, analysis of subpopulations of the PMA-treated Jurkat cells revealed that the steady-state responses of both JNK and CD69, a T cell surface activation marker, were essentially all-or-none in character. These studies show that the JNK cascade commonly exhibits switch-like responses to a variety of stimuli.

Bet-hedging and epigenetic inheritance in bacterial cell development

“…Importantly, such feedback-based switches can generate bistability; i.e., the occurrence of two distinct subpopulations that exhibit different phenotypes within the isogenic population (2). Maturation in developing oocytes in Xenopus embryos is governed by a bistable switch, and the Hedgehog network, responsible for cellular differentiation in a diversity of eukaryotes, involves bistable switching as well (3,4). These types of regulatory switches are also found in single-celled organisms such as yeasts and bacteria, where they lead to phenotypic variability within the isogenic population (2).…”

A model for restriction point control of the mammalian cell cycle

“…The kinetics of MAP-kinase signaling has been studied in great detail by Ferrell (Bagowski et al, 2003), who has shown convincingly that this signaltransduction pathway functions as a bistable switch in frog eggs. According to Ferrell's evidence, the switch is created by a positive-feedback loop superimposed on a highly nonlinear (sigmoidal) signal-response curve of the kinase cascade (Ferrell and Machleder, 1998;Ferrell, 2002).…”

Jun NH 2 -terminal kinase (JNK) prevents nuclear β-catenin accumulation and regulates axis formation in Xenopus embryos

“…It has been suggested that a high level of JNK activity may induce the degeneration of unhealthy oocytes (17). However, this suggestion cannot explain the functions of maternal JNK signaling in healthy Xenopus embryos (18).…”