Regulation of MAP kinases by docking domains

In order to adapt to their environment, cells inte-grate extracellular signals through activation of numer-ous signal transduction pathways that regulate theirmorphology, proliferation, differentiation and survival.The MAP kinases play a central role in these differentprocesses in mammals as well as in other eucaryotes.Extra cellular stimuli initiate cascades of events, which,ultimately, result in the activation of one or moresubset of MAP kinases families (Widmann et al., 1999).To date, five distinct groups of MAP kinases havebeen characterized. The ERK 1/2 (extra-cellular signal-related kinases); JNK 1/2/3 (c-jun amino-terminal ki-nases); p38α, 2, γ, δ; ERK3/4 and ERK5 (Cobb, 1999;Davis, 2000; Nebreda and Porras, 2000; Widmann et al.,1999). The most studied MAPK are the ERK1/2, JNKand p38 MAP kinases. It is generally accepted that, invitro, the ERKs are preferentially activated in responseto growth factors and phorbol esters and associatedwith proliferation and differentiation, while the JNKand p38 MAP kinases are more responsive to a diverseset of stress stimuli ranging from osmotic shock tocytokine stimulation (Pearson et al., 2001).Although one landmark of the MAP kinases is thecomplexity of the signaling cascades that lead to theiractivation, the organisation of these cascades is simpleand conserved between the different families (Wid-mann et al., 1999). Each family of MAP kinases iscomposed of a module of three kinases: a MAP kinasekinase kinase (MAPKKK), which phosphorylates andactivates a MAP kinase kinase (MAPKK), which inturn phosphorylates and activates a MAP kinase(MAPK). MAPKKK, which are serine/threonine ki-nases, are activated after phosphorylation (by ste20-like kinases) or by their interaction with a small GTP-binding protein of the Ras or the Rho family inresponse to extra cellular stimuli (Dan et al., 2001;Kolch, 2000). Activated MAPKs are present in thenucleus where they phosphorylate transcription factors(Brunet et al., 1999; Chen et al., 1992; Gonzalez et al.,1993; Lenormand et al., 1993). The proposed regulatorymechanisms of subcellular localisation upon activationvary depending on the MAPK (Adachi et al., 1999;Adachi et al., 2000; Ben-Levy et al., 1998; Cobb andGoldsmith, 2000; Engel et al., 1998; Tolwinski et al.,1999). In any case, once activated, MAPK phosphory-late a wide range of substrates in various cellularcompartments. To date 14 MAPKKK, 7 MAPKK and 12MAPK have been identified in mammalian cells. Overthe past few years, genetic and pharmacological ap-proaches have been essential to gain information onthe physiological roles of the different MAP kinases(Chang and Karin, 2001; Cohen, 1999). Specific inhibi-tors of enzymes from the MAPK families have beenwidely used in cell culture and in animals (Awad et al.,2000; Barone et al., 2001; Cohen, 1997). Some of the