![]() ![]() Switching occurred even if the level of input MAP3K was ramped up steadily and gradually. They showed that the output of the cascade (activated MAPK) was relatively insensitive to low levels of input noise (a property known as thresholding), but increased much more suddenly once a certain threshold of input had been reached (a property known as switching, or ‘ultrasensitivity’). ![]() Using a cascade that could rapidly amplify some spurious noise into a full-blown response seemed a poor way to make such decisions.īeginning in 1996, in a series of important papers, Jim Ferrell and colleagues proposed that the MAPK cascade was not an amplifier, but a switch. ‘to divide or not?’, ‘to differentiate or not?’ and even ‘to be or not?’. These pathways are primarily involved in binary decision making, e.g. However, it was not clear that MAPK-mediated growth factor and developmental signaling had similar needs for speed and amplification. This concept originated during studies of the prototypical kinase cascade that, during ‘fight or flight’, responds to small amounts of adrenaline by quickly releasing a lot of sugar into the bloodstream. Thus began the idea of a conserved signaling module that must carry out some evolutionarily conserved function.īut what function? Why arrange proteins in a cascade? The textbook wisdom at the time pointed to signal amplification, with each activated kinase molecule in a given tier activating multiple kinase molecules in the next tier, like a triangular cascade of dominoes. Subsequent studies showed that not only were the components of MAPK pathways conserved between yeast and humans, but also their arrangement into a cascade was conserved. ![]() In the early 1990s, when components of mammalian MAPK cascades were cloned, it was discovered that they were highly homologous to several yeast kinases (Ste11 MAP3K, Ste7 MAP2K, Kss1 MAPK and Fus3 MAPK) known to function in the signal transduction pathway by which yeast cells respond to peptide mating pheromone. The module consists of a MAP3K, which phosphorylates and thereby activates a MAP2K, which in turn phosphorylates and activates a MAPK. MAPK cascades are found embedded in signaling networks that transmit many different signals, including those initiated by growth and development factors, inflammatory stimuli, and cellular stresses. Do modules like kinase cascades always carry out similar functions regardless of which signaling pathway they are placed in? If not, what are the mechanisms that modulate kinase function to allow different input–output mappings? In a recent issue of Current Biology, Takahashi and Pryciak show that a scaffold protein can counteract the switch-like tendencies of the MAPK cascade to allow graded signaling, essentially turning an on–off switch into a dimmer. More recently, eukaryotic mitogen-activated protein kinase (MAPK) cascades have been shown to be inherently switch-like. Indeed, when the first protein kinase cascade was discovered, it was hypothesized to function as an amplifier. Like electronic circuits, intracellular signal transduction networks also appear to contain modular elements, such as protein kinase cascades. The individual elements in an electronic circuit can be analyzed in terms of how they convert input into output. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |