Volume 81, Number 9
CENEAR 81 9 p. 55
ISSN 0009-2347
SIGNALING NETWORKS Small-molecule-based investigations of membrane-to-nucleus signaling and chromatin function suggest the existence of network motifs that ensure robustness, adaptability, and switchlike behavior, as well as other striking commonalities (the signaling network model of chromatin).25 The figure uses the platelet-derived growth factor receptor (PDGFR) and a nucleosome to illustrate that similar principles underlie information transfer in the cytoplasm and nucleus of cells. When the extracellular growth factor PDGF binds to its receptor outside of a cell, it dimerizes the receptor. The result is to create a high effective molarity of one receptor tail in the vicinity of the other. Since the tails have tyrosine kinase activities, their proximal relationship facilitates trans-phosphorylation. These phosphorylations take place within flexible regions of the tails, and the phosphate groups complete binding sites for intracellular signaling proteins that have substrates that reside within the inner leaflet of the plasma membrane. The docking of the lipid kinase PI3K, for example, facilitates the phosphorylation of its substrate, the membrane component phosphatidyl inositol-4.5-bisphosphate. A series of subsequent events all proceed by this type of induced proximity, allowing the signal to eventually reach the nucleus. The new insight is that induced proximity is the key to information transfer within chromatin, and that docking sites created when the signal reaches chromatin in the nucleus mediate network behavior. For example, the cytoplasmic signal is received in the form of a histone acetyl transferase (HAT), which deposits an acetyl group on a specific lysine side chain of a nucleosome in the vicinity of a target gene. This completes a binding site for a signaling protein SWI/SNF (pronounced switch-sniff) that, after docking, remodels its now nearby nucleosome substrate. This ATP-driven motor protein mechanically loosens the nucleosome so that the transcription apparatus can access the promoter of a target gene. Small-molecule-based investigations of both networks helped illuminate their fundamental operating principles.
IMAGE COURTESY OF STUART SCHREIBER, HARVARD UNIVERSITY
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