Plant mitogen-activated protein kinase cascades: Negative regulatory roles turn out positive.

M itogen-activated protein (MAP) kinase cascades are a standard player in the signal transduction literature for diverse organisms (1–3). Previous work has shown that specific MAP kinases become activated during plant responses to pathogens, suggesting a role for MAP kinase cascades in disease resistance. However, no function-blocking experiments had demonstrated a causal role until the work of Frye et al. (4) on the Arabidopsis EDR1 gene that was presented in a recent issue of PNAS. In a related development, Petersen et al. (5) have just published work showing that disruption of the Arabidopsis MPK4 MAP kinase gene also alters plant defense activation. It is surprising that, for all plant species, these are only the second and third characterized mutants known to carry a disrupted kinase from a MAP kinase cascade. Equally striking, both papers revisit a theme established by the first known plant MAP kinase cascade mutant and reinforced in a separate study (6, 7): the MAP kinase cascade as a negative regulator of the relevant biological response. However, the probability of crosstalk among MAP kinase cascades, discussed below, suggests that this negative regulatory activity of MAP kinase cascades could be misleading. MAP kinase cascades, which transduce a wide variety of extracellular signals, are known as much for their laborious acronyms as for their important biological functions. MAP kinase kinase kinase (MAPKKK) proteins, including Raf-like kinases and MEKK proteins, phosphorylate MAP kinase kinases (MAPKKs, or MEKs) that phosphorylate MAP kinase (MAPK) proteins. Upon activation, MAPKs are often transported to the nucleus where they phosphorylate specific transcription factors. No single plant MAP kinase cascade has been characterized to the extent that a functional relationship among three sequential kinase participants has been confirmed (3). However, numerous plant gene products with the conserved residues of these kinases have been identified, activation of specific MAPK proteins has been observed in plants responding to hormones or environmental stimuli such as cold, touch, infection or wounding, and some plant MAPKs, MAPKKs, or MAPKKKs have been shown to complement yeast mutants at the appropriate level of the yeast kinase cascades (3). Until now, most plant MAPK proteins have been implicated in a particular biological response solely because of their activation during that response. Previously, the only known mutations affecting a protein kinase from a plant MAP kinase cascade disrupted Arabidopsis CTR1, which encodes a Raf-like MAPKKK protein (6). Arabidopsis ctr1 mutants exhibit constitutive activation of ethylene hormone–response pathways. Exposure to ethylene is hypothesized to inactivate a CTR1 MAP kinase cascade, triggering plant ethylene responses (8). The importance of ethylene in plant biology has prompted extensive, near-saturating, and very successful mutational analysis in Arabidopsis, and it is intriguing that