Long‐range signaling by phosphoprotein waves arising from bistability in protein kinase cascades

Markevich, N I; Tsyganov, M. A.; Hoek, Jan B.; Kholodenko, Boris N.

doi:10.1038/msb4100108

Cited by 82 publications

(84 citation statements)

References 30 publications

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“…This termination of signaling by phosphatases necessitates mechanisms to facilitate signal propagation across a cell. In fact, recent experimental and theoretical work showed that endocytosis, scaffolding, molecular motors, and traveling waves of phospho-proteins are involved in the propagation of signals to different cellular locations [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Signaling cascades as cellular devices for spatial computations

Stelling

Kholodenko

2008

J. Math. Biol.

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Signaling networks usually include protein-modification cycles. Cascades of such cycles are the backbones of multiple signaling pathways. Protein gradients emerge from the spatial separation of opposing enzymes, such as kinases and phosphatases, or guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) for GTPase cycles. We show that different diffusivities of an active protein form and an inactive form leads to spatial gradients of protein abundance in the cytoplasm. For a cascade of cycles, using a discrete approximation of the space, we derive an analytical expression for the spatial gradients and show that it converges to an exact solution with decreasing the size of the quantization. Our results facilitate quantitative analysis of the dependence of spatial gradients on the network topology and reaction kinetics. We demonstrate how different cascade designs filter and process the input information to generate precise, complex spatial guidance for multiple GTPase effector processes. Thus, protein-modification cascades may serve as devices to compute complex spatial distributions of target proteins within intracellular space.

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Section: Discussionmentioning

confidence: 99%

Signaling cascades as cellular devices for spatial computations

Stelling

Kholodenko

2008

J. Math. Biol.

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“…In reality, however, the signaling behavior is highly complex (Oda and Kitano, 2006) due to the dynamical interaction of the various intracellular molecules and pathways. To approach the non-intuitive character of signaling pathways, we therefore require systematic methodologies that incorporate both biological and theoretical methods to interpret signaling dynamics (Gilchrist et al, 2006;Markevich et al, 2006;Selvarajoo, 2006;Alon, 2007;Basak et al, 2007;Kholodenko, 2007). Recently, there have been such attempts to understand the signaling dynamics of TLRs (Covert et al, 2005;Selvarajoo, 2006).…”

Section: Systems Biology Approach To Tlr4 Signalingmentioning

confidence: 99%

Toll-like receptor signal transduction

Krishnan

Selvarajoo²,

Tsuchiya³

et al. 2007

Exp Mol Med

213

171

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“…This lack of temporal resolution prevented to investigate whether mitochondrial permeabilization is subject to spatial coordination by processes such as localized production of signaling molecules and/or diffusion, which were previously described as important regulators of other cellular signaling pathways, such as the forwarding of phosphorylation signals and Ca 2 þ waves. [15][16][17] We here describe a novel approach combining rapid cellular imaging and computational modeling to remedy this limitation in the analysis of apoptotic signaling. Taking advantage of the synchrony of sibling cells in apoptosis onset, we established an imaging technique that is capable of predicting the time of MOMP for individual cells with high probability.…”

mentioning

confidence: 99%

Dynamics of outer mitochondrial membrane permeabilization during apoptosis

et al. 2009

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Individual cells within a population undergo apoptosis at distinct, apparently random time points. By analyzing cellular mitotic history, we identified that sibling HeLa cell pairs, in contrast to random cell pairs, underwent apoptosis synchronously. This allowed us to use high-speed cellular imaging to investigate mitochondrial outer membrane permeabilization (MOMP), a highly coordinated, rapid process during apoptosis, at a temporal resolution approximately 100 times higher than possible previously. We obtained new functional and mechanistic insight into the process of MOMP: We were able to determine the kinetics of pore formation in the outer mitochondrial membrane from the initiation phase of cytochrome-c-GFP redistribution, and showed differential pore formation kinetics in response to intrinsic or extrinsic apoptotic stimuli (staurosporine, tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL)). We also detected that the onset of mitochondrial permeabilization frequently proceeded as a wave through the cytosol, and that the frequency of wave occurrence in response to TRAIL was reduced by inhibition of protein kinase CK2. Computational analysis by a partial differential equation model suggested that the spread of permeabilization signals could sufficiently be explained by diffusion-adsorption velocities of locally generated permeabilization inducers. Taken together, our study yielded the first comprehensive analysis of clonal cell-to-cell variability in apoptosis execution and allowed to visualize and explain the dynamics of MOMP in cells undergoing apoptosis. Apoptosis is an evolutionary conserved cell death process that is fundamental to remove superfluous and damaged cells from the bodies of multicellular organisms. Impaired or excessive apoptosis has repeatedly been implicated as a major contributor to proliferative and degenerative diseases. Initiated by BH-3-only proteins of the Bcl-2 protein family, mitochondrial outer membrane permeabilization (MOMP) and the subsequent activation of effector caspases are rapid key processes crucial for the efficient execution of apoptotic cell death.Previous single-cell imaging studies using fluorescently tagged proteins showed that MOMP results in the coordinate release of mitochondrial intermembrane space proteins, including cytochrome-c (cyt-c) and Smac/Diablo, into the cytosol. The release was suggested to occur synchronously throughout the cytosol and with very fast kinetics, which seemed independent of the type of the apoptotic stimulus used, and also independent of downstream effector caspase activity. [1][2][3][4][5] Cytosolic cyt-c induces the rapid formation of the large multiprotein apoptosome complex, caspase-9 activation and subsequent activation of effector caspases-3 and -7. 6,7 In parallel, cytosolic Smac neutralizes x-linked inhibitor of apoptosis protein, the key inhibitor of caspases-9, -3 and -7. 8 As long as all key components of the execution network are present, effector caspase activation proceeds as a rapid and kinetically largely i...

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Long‐range signaling by phosphoprotein waves arising from bistability in protein kinase cascades

Cited by 82 publications

References 30 publications

Signaling cascades as cellular devices for spatial computations

Signaling cascades as cellular devices for spatial computations

Toll-like receptor signal transduction

Dynamics of outer mitochondrial membrane permeabilization during apoptosis

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