Bistability from double phosphorylation in signal transduction

Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero‐order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.

[1]  R Thomas,et al.  A complex control circuit. Regulation of immunity in temperate bacteriophages. , 1976, European journal of biochemistry.

[2]  J. Ferrell.  Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. , 1996, Trends in biochemical sciences.

[3]  C. Thron,et al.  Bistable biochemical switching and the control of the events of the cell cycle* , 1997, Oncogene.

[4]  B. Kholodenko,et al.  Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades , 2004, The Journal of cell biology.

[5]  John J. Tyson,et al.  Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Ferrell.  Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. , 2002, Current opinion in cell biology.

[7]  E. Wimmer,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2022 .

[8]  H. Westerhoff,et al.  Product dependence and bifunctionality compromise the ultrasensitivity of signal transduction cascades , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  A. Ashworth,et al.  Identification of the sites in MAP kinase kinase‐1 phosphorylated by p74raf‐1. , 1994, The EMBO journal.

[10]  Katherine C. Chen,et al.  Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. , 2003, Current opinion in cell biology.

[11]  J. Lisman.  A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[12]  U. Bhalla,et al.  Emergent properties of networks of biological signaling pathways. , 1999, Science.

[13]  Chi-Ying F. Huang,et al.  Ultrasensitivity in the mitogen-activated protein kinase cascade. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[14]  James E. Ferrell,et al.  Bistability in cell signaling: How to make continuous processes discontinuous, and reversible processes irreversible. , 2001, Chaos.

[15]  J. Ferrelljr,et al.  Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs , 1996 .

[16]  D. Koshland,et al.  An amplified sensitivity arising from covalent modification in biological systems. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Prahlad T. Ram,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2002, Science.

[18]  M Laurent,et al.  Multistability: a major means of differentiation and evolution in biological systems. , 1999, Trends in biochemical sciences.

[19]  D. Koshland,et al.  Amplification and adaptation in regulatory and sensory systems. , 1982, Science.

[20]  James E. Ferrell,et al.  Mechanistic Studies of the Dual Phosphorylation of Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.