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Flipping a Signaling Switch

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Science's STKE  10 Feb 2004:
Vol. 2004, Issue 219, pp. tw54
DOI: 10.1126/stke.2192004TW54

Markevich et al. developed a computational model for a mechanism, not previously described, whereby signaling pathways can exhibit bistable behavior and switch between stable "on" and "off" states. Mitogen-activated protein kinase (MAPK) signaling pathways, which play critical roles in cell proliferation, differentiation, and apoptosis, generally function as a three-tiered cascade in which an activated (phosphorylated) kinase at one level phosphorylates and thereby activates the kinase at the subsequent level. To be fully activated, these MAPKs, MAPK kinases (MAPKKs), and MAPKK kinases must be phosphorylated at two sites. The MAPK cascades are regulated by multiple feedback loops, and the existence of either positive or double-negative feedback regulation is generally thought to be necessary for a cascade to function as a bistable system. Markevich et al., however, present a model in which bistability of the MAPK signaling pathway arises from a distributive kinetic mechanism for the dual phosphorylation and dephosphorylation of the kinase and is independent of feedback regulation. (A distributive mechanism implies that the kinase or phosphatase releases the monophosphorylated intermediate, which must then interact with enzyme again before it is converted into the final doubly phosphorylated or completely dephosphorylated state.) Their model was consistent with the reported kinetic properties of the extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphatase (MKP3). The authors suggest that multisite phosphorylation, which takes place on proteins involved in many signaling systems, may represent a widespread mechanism for conferring switch-like behavior on various signaling systems.

N. I. Markevich, J. B. Hoek, B. N. Kholodenko, Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J. Cell Biol. 164, 353-359 (2004). [Abstract] [Full Text]

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