Tài liệu Báo cáo khoa học: Effects of sequestration on signal transduction cascades docx

Effects of sequestration on signal transduction cascades

Nils Blu¨ thgen1,* Frank J. Bruggeman2

, Stefan Legewie1

, Hanspeter Herzel1

, Hans V. Westerhoff2,3

and Boris N. Kholodenko4

1 Institute for Theoretical Biology, Humboldt University Berlin, Germany

2 Department of Molecular Cell Physiology, Institute of Molecular Cell Biology, Faculty of Earth and Life Sciences, Vrije Universiteit,

Amsterdam, the Netherlands

3 Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, School of Chemistry, University of

Manchester, UK

4 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA

In most biological organisms intracellular signal pro￾cessing is carried out by networks composed of

enzymes that activate and inactivate each other by co￾valent modification. Signals received at the cell mem￾brane ripple through signalling networks via covalent

modification events to reach various locations in the

cell and ultimately cause cellular responses. The bio￾chemical building blocks of these networks are fre￾quently enzyme pairs, such as a kinase and a

phosphatase, that form covalent modification cycles in

which the target enzyme is covalently modified at sin￾gle or multiple sites in a reversible manner.

In some experiments, the stimulus–response curves

display strong sigmoidal dependencies in vivo, for

example, in the activation of the mitogen-activated

protein kinase (MAPK) cascade [2] and Sic1 [3], and

in vitro, for example, in the phosphorylation of

isocitrate dehydrogenase [4], muscle glycolysis [5] and

in postsynaptic calcium signalling [6]. Sigmoidal

stimulus–response curves imply that the responses are

highly sensitive to changes in signals around the

threshold level. Thus it is more sensitive than a typical

Michaelis–Menten-like response, a property that has

been termed ultrasensitivity [1].

Keywords

MAPK; phosphorylation; sequestration;

signal transduction; zero-order ultrasensitivity

Correspondence

N. Blu¨thgen, Institute for Theoretical

Biology, Humboldt University Berlin,

Invalidenstr. 43, 10115 Berlin, Germany

Fax: +49 30 838 56943

Tel: +49 30 838 56971

E-mail: [email protected]

*Present address

Molecular Neurobiology, Institute of Biology,

Free University of Berlin, Germany.

Note

Nils Blu¨thgen and Frank J. Bruggerman

contributed equally to this study.

(Received 21 November 2005, accepted

15 December 2005)

doi:10.1111/j.1742-4658.2006.05105.x

The building blocks of most signal transduction pathways are pairs of

enzymes, such as kinases and phosphatases, that control the activity of pro￾tein targets by covalent modification. It has previously been shown [Gold￾beter A & Koshland DE (1981) Proc Natl Acad Sci USA 78, 6840–6844]

that these systems can be highly sensitive to changes in stimuli if their cata￾lysing enzymes are saturated with their target protein substrates. This

mechanism, termed zero-order ultrasensitivity, may set thresholds that filter

out subthreshold stimuli. Experimental data on protein abundance suggest

that the enzymes and their target proteins are present in comparable con￾centrations. Under these conditions a large fraction of the target protein

may be sequestrated by the enzymes. This causes a reduction in ultrasensi￾tivity so that the proposed mechanism is unlikely to account for ultrasensi￾tivity under the conditions present in most in vivo signalling cascades.

Furthermore, we show that sequestration changes the dynamics of a cova￾lent modification cycle and may account for signal termination and a sign￾sensitive delay. Finally, we analyse the effect of sequestration on the

dynamics of a complex signal transduction cascade: the mitogen-activated

protein kinase (MAPK) cascade with negative feedback. We show that

sequestration limits ultrasensitivity in this cascade and may thereby abolish

the potential for oscillations induced by negative feedback.

Abbreviations

JAK, janus kinase; MAPK, mitogen-activated protein kinase; MAPKK, mitogen-activated protein kinase kinase; MCA, metabolic control analysis.

FEBS Journal 273 (2006) 895–906 ª 2006 The Authors Journal compilation ª 2006 FEBS 895