Mitogen-activated protein kinases: specific messages from ubiquitous messengers

摘要: Signal transduction networks allow cells to perceive changes in the extracellular environment and mount an appropriate response. Mitogen-activated protein kinase (MAPK) cascades are among most thoroughly studied of signal systems have been shown participate a diverse array cellular programs, including cell differentiation, movement, division, death. A key question studies this cascade is, how does ubiquitously activated regulatory enzume generate specific biologically response? In review we describe recent findings that provide insight into ways regulation, structure, localization MAPKs participation adapters scaffolds can help determine biological outcomes. MAPK evolutionarily conserved all eucaryotes play role regulation gene expression as well cytoplasmic activities. They typically organized three-kinase architecture consisting MAPK, MAPK activator (MEK, MKK, or kinase), MEK (MEK [MEKK] kinase). Transmission signals is achieved by sequential phosphorylation activation components respective cascade. yeast Saccharomyces cerevisiae, five modules described; they regulate mating, filamentation, high-osmolarity responses, wall remodeling, sporulation (Fig. ​(Fig.1A)1A) (reviewed references 56 77). mammalian distinguishable identified so far ​(Fig.1B).1B). These include signal-regulated 1 2 (ERK1/2) cascade, which preferentially regulates growth c-Jun N-terminal (JNK) p38 cascades, function mainly stress responses like inflammation apoptosis 57, 74, 103). Moreover, pathways control several developmental such morphogenesis spatial patterning Dictyostelium amoebae (17, 45), eye development Drosophila melanogaster (124), vulva induction Caenorhabditis elegans (113), T-cell mammals (31). FIG. 1 Schematic overview modules. (A) S. sporulation. (B) Mammalian growth, ... Individual generally independently from each other, specificity manifested distinct physiologic responses. This obvious when studying signaling cerevisiae. Here particular event characteristically activates module initiates unique program For example, stimulation with pheromone leads response pathway (STE11, STE7, FUS3) ​(Fig.2),2), ultimately results cycle arrest mating-specific genes. However, related whose share some not affected but only stimulus. under conditions high osmolarity Ste11 lead Hog1 induce Conversely, activate filamentation (which utilizes STE11 STE7) genes filamentous without triggering osmolarity. observations suggest developed efficient mechanisms successfully suppress cross talk, even individual more than one pathway. FIG. 2 Scaffold adapter molecules pathways. (gray shading) thought promote formation oligomeric complexes module. Scaffolds ... In metazoan problem complex because simultaneously exposed multiple must integrate these inputs choose Thus, context plays determinative way interpreted. although ERKs differentiation JNKs response, always case certain types proliferation (110). indicates associated be type specific. PC12 cells, transient ERK whereas sustained measured neurite outgrowth (81). contrasting physiological same context, suggesting also determined other selective module. In short review, outline advances understanding system explain regulated generated. Because power genetics, cerevisiae at advanced level, thus many examples utilize organism given. analogous appear operative metazoans well. We discuss turn enzyme-substrate interactions, scaffolding proteins, subcellular targeting localization, temporal integration determining outcome activation.