Digital kinases

Abstract

Protein kinases mediate most of the signal transduction in eukaryotic cells, controlling important cellular processes. Functioning as sensors and switches, kinases play a critical role in the regulation of cell fate decisions: proliferation, differentiation or death. Cellular sensors must have signaling properties well suited for the processing and propagation of external or internal stimuli that promote irreversible processes. These properties include ultrasensitivity, hysteresis and digital responses. Ultrasensitivity means to produce a very large response to a small increase in stimulus after a threshold is crossed, hysteresis (a form of biochemical memory) means sustained activation when the stimulus has disappeared, and digital is an all-or-none response at a single cell level. These properties are present in JNK, a stress protein kinase that regulates cell death. In a recent article, we have characterized Xenopus AMPK, a stress protein kinase that controls energy levels in the cell, showing that is regulated similar to the mammalian ortholog. By using Xenopus oocytes we studied the AMPK signaling system and compared to JNK. Our work showed that AMPK is ultrasensitive to an apoptotic stimulus (hyperosmolar sorbitol) but, in contrast to JNK, does not show hysteresis. By single cell analysis we found that the response of AMPK and JNK to hyperosmolar sorbitol is all-or-none (digital) in character, and that initial graded responses of both protein kinases are converted into digital during the critical period of cytochrome c release. We proposed a model to explain the cell death program as integration of multiple digital signals from stress sensors, that now I extend to a more general model for sensing, integrating and making choices in the cell and the organism.

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Acknowledgements

This work was supported by Grant PI 05/1748 from Fondo de Investigaciones Sanitarias (FIS). J.M.L. is recipient of a contract from the “Programa Ramón y Cajal” (MEC).

Figures and Tables

Figure 1 A digital model for initiation of the cell death program. Single cell response to stress (hyperosmolar sorbitol) is ultrasensitive and graded for 2 h, and then a critical period starts where the activity achieved is compared with specific threshold levels for each protein kinase. Kinase activity under the threshold level returns to basal state, whereas activation over the threshold level remains high in the critical period. When we analyze individual oocytes at 4 h, a digital response is obtained, but at 2 h the response is analog. The cell would integrate multiple digital signals (PK X represents one or more protein kinases) for the critical period evaluating whether to trigger a cell death program.

Figure 2 Life as a chip: A digital model for cell decisions. Different stimuli (inputs) are sensed by ultrasensitive protein kinases producing a plethora of analog signals, and some of them are converted into digital signals. The digital responses obtained by the network of kinases are integrated and defines a cellular program, which is translated into a cell decision (outputs). Thus, the generation of digital responses by protein kinases might be the basis for important biological processes: from development to memory (see text).

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