▲ FIGURE 13-9 Clustering of membrane proteins mediated by cytosolic adapter proteins containing multiple protein-binding domains. The PDZ domain, which binds to certain C-terminal sequences, and the SH3 domain, which binds to proline-rich sequences, are two of several conserved domains that participate in protein-protein interactions. (a) Three-dimensional surface structure of a PDZ domain showing the backbone of the bound target peptide in red. Regions in the PDZ domain that bind the COO- group and side chain of the C-terminal residue are colored yellow and blue, respectively. The binding pocket for the residue two distant from the C-terminus (P-2) is green. (b) Schematic diagram of protein-protein interactions that cluster several different membrane proteins in a postsynaptic segment of a nerve cell and anchor the resulting

Appropriate Cellular Responses Depend on Interaction and Regulation of Signaling Pathways

In this chapter and the next, we focus primarily on simple signal-transduction pathways triggered by ligand binding to a single type of receptor. Activation of a single type of receptor, however, often leads to production of multiple second messengers, which have different effects. Moreover, the same cellular response (e.g., glycogen breakdown) may be induced by activation of multiple signaling pathways. Such interaction of different signaling pathways permits the fine-tuning of cellular activities required to carry out complex developmental and physiological processes.

The ability of cells to respond appropriately to extracellular signals also depends on regulation of signaling pathways themselves. For example, once the concentration of an external signal decreases, signaling via some intracellular pathways is terminated by degradation of a second messenger; in other pathways, signaling is terminated by deactivation of a signal-transduction protein. Another important mechanism for as-

complex to cytoskeletal actin filaments. Within the adapter protein PSD-95, two of the three PDZ domains shown and one SH3 domain bind three different membrane proteins into one complex. The guanylate kinase (GuK) domain of the PSD-95 protein links the complex, via several intervening adapter proteins (including one also containing PDZ and SH3 domains), to fibrous actin underlying the plasma membrane. Neuroligin is an adhesive protein that interacts with components of the extracellular matrix. Ank = ankyrin repeats. Other multibinding adapter proteins localize and cluster different receptors in the synaptic region of the plasma membrane. [Part (a) adapted from B. Harris and W. A. Lim, 2001, J. Cell Sci. 114:3219; part (b) adapted from C. Garner, J. Nash, and R. Huganir, 2000, Trends Cell Biol. 10:274.]

suring appropriate cellular responses is desensitization of receptors at high signal concentrations or after prolonged exposure to a signal. The sensitivity of a cell to a particular signaling molecule can be down-regulated by endocytosis of its receptors, thus decreasing the number on the cell surface, or by modifying their activity so that the receptors either cannot bind ligand or form a receptor-ligand complex that does not induce the normal cellular response. Such modulation of receptor activity often results from phosphorylation of the receptor, binding of other proteins to it, or both. We examine the details of various mechanisms for regulating signaling pathways in our discussion of individual pathways.

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