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For example, receptor tyrosine kinases provide a prime example of how a scaffold can allow a single input to ramify into several signaling pathways.Nebivolol hydrochloride Another important purpose of scaffolding molecules is to prevent cross talk between different pathways that share components.Scaffold molecules for MAPK pathways also exist in mammalian cells.An interesting aspect of the arrestin scaffold is that it causes relocalization of the signaling components from the cytoplasm to the plasma membrane and thence to endosomes; this process seems to be critical to the signaling events in this pathway.Since scaffold proteins cause cosegregation of components of MAPK pathways, it has often been assumed that this results in signal amplication.However, recent analyses have suggested that the situation is far more complex and that either enhancement or inhibition of signaling can occur, depending on the relative amounts of the active signaling components and the scaffold. The presence of an excess of scaffold molecules can lead to the separation of the active components into nonfunctional complexes, and thus to reduction of signaling activity.Localization of signaling components to specialized cellular structures is another important function for scaffold proteins.Perhaps the best examples of this relate to signaling structures in the central nervous system or sensory organs.Another important PDZ domainbased signaling entity involves ligandgated ion channels located in neural synapses and their associated postsynaptic density molecules.The NR subunit of the NMDA receptor also participates in signal complex assembly and can link to the cytoskeleton via association with actinin.Yotiao also binds the protein phosphatase PP, which can inactivate the NMDA receptor. Thus the postsynaptic density is comprised, in part, of an elaborate Cabazitaxel network of signaling proteins colocalized via various scaffolding molecules with the ligandgated ion channels at the synapse.No discussion of signaling scaffolds would be complete without mention of caveolae.These cholesterolrich membrane rafts are organized by the caveolin and proteins.Thus, caveolae may serve to preassemble signaling complexes at the plasma membrane where they may subsequently be efciently activated. In summary, scaffold proteins can serve a variety of purposes including signal diversication, signal amplication, prevention of cross talk, anchoring of signaling components at specialized subcellular sites, and relocalization of active molecules during the signaling process.A very comprehensive review has cataloged a large number of instances where signaling components are associated with actin or tubulinbased structures, or where such structures inuence the activity of the signaling molecule. These multiple examples of cytoskeletal effects on signaling probably reect a number of underlying mechanisms, most of which remain obscure.Here I would like to propose a mechanistic rationale for one important example of cytoskeletal effects on signaling.The common theme seems to be a substantial perturbation of the organization of the actin lament system, particularly cortical actin. Further mechanistic insights into these events have been gleaned through some very recent studies from my laboratory.Thus, we found that either inhibition of protein kinase A permitted persistent signaling to MAPK in cells held in suspension. Furthermore, activated PKA can phosphorylate and inactivate PAK, while the effects of PKA inhibition or PAK activation on signaling to MAPK could be completely reversed by treatment with cytochalasin D.

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