MAP kinase pathways

Abstract

Mitogen-activated protein kinase (MAPK) pathways regulate diverse processes ranging from proliferation and differentiation to apoptosis. Activated by an enormous array of stimuli, they phosphorylate numerous proteins, including transcription factors, cytoskeletal proteins, kinases and other enzymes, and greatly influence gene expression, metabolism, cell division, cell morphology and cell survival.FIG1Each MAPK pathway contains a three-tiered kinase cascade comprising a MAP kinase kinase kinase (MAPKKK, MAP3K, MEKK or MKKK), a MAP kinase kinase (MAPKK, MAP2K, MEK or MKK) and the MAPK. This three-tier module mediates ultrasensitive switch-like responses to stimuli (Ferrell, 1996). Frequently, a MAPKKK kinase (MAPKKKK, MAP4K or MKKKK) activates the MAPKKK. The MAPKKKK or MAPKKK can be linked to the plasma membrane – for example, through association with a small GTPase or lipid (e.g. Ste20, PKC, PAK MAPKKKKs and Raf MAPKKKs).Numerous different MAPKKKs exist, including Raf isoforms, Ste11 relatives MEKK1-MEKK4, mixed lineage kinases (MLKs), Tao proteins and Mos. The MAPKKs and MAPKs are more highly related (Caffrey et al., 1999; Chen et al., 2001; Uhlik et al., 2005). The MAPKKKs can have large regulatory domains that interact with upstream regulators (e.g. Rho, Ras), have functions such as ubiquitylation and are activated by relief of autoinhibition and oligomerization. MAPKKs typically have smaller regulatory domains and are activated by dual phosphorylation of serine and threonine residues within the activation loop of the catalytic domain. They exhibit great specificity for their cognate MAPK but are regulated by many MAPKKKs.MAPKs are activated by dual phosphorylation of conserved threonine and tyrosine residues within the activation loop (denoted T-X-Y) and phosphorylate targets on serine and threonine residues within a consensus PXT/SP motif (X can depend on the MAPK) (Songyang et al., 1996; Chen et al., 2001). Pathway specificity is regulated at several levels, including kinase-kinase and kinase-substrate interactions, colocalization of kinases by scaffold proteins, and inhibition of cross-talk/output by the MAPKs themselves. Scaffolds regulate MAPK signaling in multiple ways beyond simple tethering (Burack and Shaw, 2000; Elion, 2001).MAPKs bind stably to substrates, MAPKKs and scaffold proteins through multiple docking domains (e.g. CD) distinct from their active sites that can recognize homologous sites on different targets (e.g. D and FXF domains), which raises the question of how this influences signaling (Chang et al., 2002; Tanoue and Nishida, 2003). MAPKs can also inhibit signaling by binding substrates when catalytically inactive (Madhani and Fink, 1998). MAPKs are attenuated by dual specificity MAPK phosphatases (MKPs), tyrosine phosphatases and serine/threonine phosphatases (Keyse, 2000). Continuous basal repression of MAPKs by phosphatases occurs and may poise a pathway for activation above a particular threshold.Signaling complexes of MAPK module components can vary with time and location. Active MAPKs frequently translocate from the cytoplasm to the nucleus to phosphorylate nuclear targets, and MAPKKs can shuttle in and out of the nucleus carrying the MAPK as a passenger and anchor them in the cytoplasm. MAPK scaffold proteins may function similarly (Elion, 2001). MAPKs localize to numerous subcellular structures, including microtubules, endosomes, the ER and the actin cytoskeleton. MAPK phosphatases may attenuate MAPKs in a site-specific manner.All Saccharomyces cerevisiae MAPK pathways were defined genetically. Although components are shared between different pathways, erroneous crosstalk does not occur. This is because of insulation mechanisms that result in exquisite specificity. The mating pathway was the first MAPK module to be defined, sequence similarity between the Ste11 MAPKKK and Ste7 MAPKK and their mammalian equivalents aiding cloning of the latter.Five MAPK pathways, utilizing six MAPKs have been defined: the Fus3 and Kss1 MAPKs are most similar to mammalian ERK1/2; the Hog1 MAPK is most similar to mammalian p38; and the Mpk1 (also known as Slt2) Mpl1 and Smk1 MAPKs, which are distinct (Caffrey et al., 1999). Fus3 and Kss1 regulate mating in response to peptide mating pheromones and have shared and unique substrates but only Fus3 is essential for mating, Kss1 functions in additional pathways that regulate invasive growth/pseudohyphal development and cell wall integrity (Wang and Dohlman, 2004; Bardwell, 2005; Elion et al., 2005). Hog1 regulates intracellular osmolarity in response to extracellular osmolarity and citric acid stress, Mpk1 regulates cell integrity and budding in response to mechanical changes at the cell wall/plasma membrane (with undefined input by Mpl1) and Smk1 regulates sporulation, being expressed only after meiosis has been initiated in response to carbon and nitrogen deprivation. Fus3 is activated by the MAPKK Ste7 on the Ste5 scaffold through localizing