Systems Biology of Cell Signaling: Recurring Themes and Quantitative Models by James E. Ferrell

Author:James E. Ferrell
Language: eng
Format: epub
Publisher: CRC Press
Published: 2021-08-12T12:00:00+00:00

7.1 CASCADES CAN DELIVER SIGNALS FASTER THAN SINGLE SIGNAL TRANSDUCERS

As a thought experiment, suppose that nature dispensed with the three-kinase cascade and instead had the first kinase—e.g., Raf in the Raf/MEK/ERK cascade—directly regulate some terminal effectors. There would be a number of advantages to this stripped-down arrangement. Only one protein kinase would need to somehow be insulated from off-target upstream regulators and only one protein kinase would need to be prevented from regulating off-target downstream substrates. If every component in a cascade possesses some vulnerabilities, then the smaller the number of levels in the cascade, the fewer the vulnerabilities.

But there are potential advantages to the three-kinase system too; one such advantage is the speed with which it can regulate abundant terminal effectors. To see why this is so, suppose that in our hypothetical one-kinase cascade, some modest concentration of active Raf—say 10 nM—must regulate substrates whose total concentration is 1,000-fold higher (10 µM). Furthermore, let us assume that the phosphatases acting on these substrates are low in activity compared to the fully active Raf protein, so that the phosphorylation reaction goes to completion as rapidly as possible. The maximum speed (kcat) of a protein kinase is typically about one phosphorylation reaction per molecule per second, and if Raf was functioning at this maximum speed, it would take 1,000 s, or about 17 min, for Raf to phosphorylate all of its substrate molecules (Figure 7.2a).

FIGURE 7.2 Magnitude amplification from a protein kinase cascade. (a) A single protein kinase could eventually phosphorylate even very abundant substrate proteins, but it would take some time. At a constant speed of 1 phosphorylation per kinase molecule per second, it would take ~17 min for 10 nM Raf to phosphorylate a 1000× excess of substrates. (b) A three-kinase cascade can phosphorylate abundant substrates much faster. At a speed of 1 phosphorylation per kinase molecule per second, it would take the cascade less than 30 s to phosphorylate the same number of substrate molecules. (c) Time courses for substrate phosphorylation by a single kinase (blue) or a three-kinase cascade (red). Here the assumed abundances are Raf, 10 nM; MEK, 1,000 nM; and ERK, 1,000 nM. The assumed KM values for all three kinases are 500 nM and the assumed kcat values for all three kinases are 1 s−1. The inset highlights the first 5 s of the time course. Next, let us consider the actual system, where Raf sits at the top of a three-kinase cascade. For simplicity, assume that each kinase in the cascade is regulated by a single phosphorylation. In the first 10 s, 10 nM Raf operating at maximal velocity could activate 100 nM MEK. In the next 10 s, those activated MEK proteins could activate a total of 1 µM ERK—less than 10 s, actually, since some of the MEK molecules will be active before the first 10 s is up. The active ERK could regulate 10 µM substrate proteins in the next (less than) 10 s. Hence in less than 30 s the three-kinase cascade could accomplish what it would take 17 min for a single kinase to do (Figure 7.

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