18.7 The Kinome

285

(which might itself be a kinase) can have a profound impact on its activity: typically,

phosphorylation activates an enzyme that is otherwise catalytically inert. The reverse

reaction, dephosphorylation, is carried out by enzymes called phosphatases. ²¹

The propagation of the signal can be described by a hidden Markov model

(Sect. 17.5.2). Let the substrate of a kinase (e.g., MAPK) be denoted by X and the

phosphorylated substrate by XP. When a kinase is in its resting, inactive form, the

following would be a reasonable guess at the transition probabilities:

StartLayout 1st Row 1st Column right arrow 2nd Column upper X 3rd Column XP 2nd Row 1st Column upper X 2nd Column 1.0 3rd Column 0.0 3rd Row 1st Column XP 2nd Column 0.9 3rd Column 0.1 EndLayout

→X XP

X 1.0 0.0

XP 0.9 0.1

(18.6)

since the phosphatases are permanently active. However, if the MAPK is itself phos-

phorylated, the transition probabilities change:

StartLayout 1st Row 1st Column right arrow 2nd Column upper X 3rd Column XP 2nd Row 1st Column upper X 2nd Column 0.0 3rd Column 1.0 3rd Row 1st Column XP 2nd Column 0.9 3rd Column 0.1 EndLayout period

→X XP

X 0.0 1.0

XP 0.9 0.1

.

(18.7)

The phosphorylation of the MAPK itself can be represented as a Markov chain and, if

X is itself a kinase, the transition probabilities for the phosphorylation of its substrate

will also be different for X and XP. The necessity of the phosphatases (whose effect

is represented by the transition probability p Subscript XP right arrow upper XpXP→X) is clearly apparent from this

scheme, for without them the supply of substrate would be quickly exhausted.

An insidious form of toxicity is engendered by molecules capable of more or less

indiscriminate phosphorylation of proteins. The extreme importance of phosphory-

lation for, especially, intracellular communication suggests that if such molecules

penetrate into the body they are likely to wreak havoc on intracellular signalling.

As already mentioned, the dephosphorylating phosphatases are permanently active,

but some of the anomalously phosphorylated molecules might not be substrates

for them. Furthermore, the phosphorylation takes time and if the upset is great

enough, the damage might become irreversible. Organophosphorus compounds caus-

ing organophosphate-induced delayed neuropathy (such as some tricresyl phosphate

isomers, diisopropyl fluorophosphate, a nerve gas, and Mipafox, an insecticide) are

candidates for the disruptive phosphorylation of kinases. ²²

The organization of kinases into signalling cascades, in which a phosphorylated,

hence activated, enzyme itself phosphorylates and activates another kinase, is char-

acteristic. One of the consequences of such cascades is the great amplification of the

initial signal (which might have been a single molecule). This is a robust method

for overcoming noise (cf. Sect. 7.6). A cascade also achieves fanout, familiar to the

21 See Johnson and Hunter (2005) for a review of experimental methods for determining

phosphorylation.

22 Lapadula et al. (1992).