Receptor signaling complexes activated

Dimerization allows the kinase activity of both intracellular chains to encounter target sequences on the other, linked receptor molecule. This enables the intermolecular cross-phosphorylation of several tyrosine residues (Figure 8.2). The phosphorylated dimer then constitutes the active receptor. It possesses an array of phosphotyrosines that enable it to bind proteins to form receptor signaling complexes. Additionally, the dimerized and phosphorylated receptor has the potential of phospho-rylating its targets. 

Takesono A, Nowak MW, Cismowski M, Duzic E, Lanier SM (2002) Activator of G-protein signaUng 1 blocks GIRK channel activation by a G-protein-coupled receptor apparent disruption of receptor signaling complexes. J Biol Chem 277 13827-13830... 

Randal, M., and Kossiakoff, A. A. (2001). The structure and activity of a monomeric interferon-gamma alpha-chain receptor signaling complex. Structure (Camb) 9(2), 155-163. 

While the current structural and functional studies have shed lights on the molecular mechanisms of post-receptor signal transduction by the TNFR superfamUy, many important questions remain. One such question is the structural basis for the formation of death receptor signaling complexes, involving DD-DD and DED-DED interactions. Another question is the molecular basis of TRAP downstream signaling. Does it involve oligomerization and proximity induced activation of down-stream effectors, or conformational modulations Because of the importance of the TNFR superfamily in human disease, an ultimate question lies on the translation of structural and functional studies into therapeutic applications. 

VanArsdale, T. L., VanArsdale, S. L., Force, W. R., Walter, B. N., Mosialos, G., Kieff, E., Reed, J. C., and Ware, C. F. (1997). Lymphotoxin-/ receptor signaling complex Role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kB. PNAS 94, 2460-2465. 

Fig. 13.6 Control of caspases by inhibitors in oMyc-induced proliferation. Caspase inhibitors (lAPs) are inactivated by phosphorylation by ASK-1. ASK-1 is an apoptotic signal-regulated protein kinase, which binds to the CD95iyCD95 ligand-receptor complex with the help of a special linker protein. Interaction with the receptor-ligand complex activates the kinase and shuts off the caspase Inhibitors (lAPs), by phosphorylation. The caspase is activated and blocks Bcl-2, (which normally prevents apoptosis), seiKling the cell towards apoptosis.

FIGURE 11.16 Schematic diagram of seven transmembrane receptor signaling pathways. Activation of G-proteins results in a rapid transient intracellular response. Agonist-activated receptors also may bind P-arrestin and internalize to form an intracellular complex for kinases that produce long-term signals involved in transcription. Separate agonist assays may be required to visualize each of these activities. 

Adaptor protein, containing one SH2 and two SH3 domains, which assembles signaling complexes at receptors. Particularly important for activation of the Ras-MAP kinase pathway. 

Ubiquitin modification of substrates can be sensed by proteins, which serve as ubiquitin receptors. These proteins harbor domains capable of ubiquitin binding and help to translate the signal into the proper physiological response by forming signaling complexes or activating downstream effectors. So far more than 15 different ubiquitin recognition motifs have been identified. 

The smooth muscle cell does not respond in an all-or-none manner, but instead its contractile state is a variable compromise between diverse regulatory influences. While a vertebrate skeletal muscle fiber is at complete rest unless activated by a motor nerve, regulation of the contractile activity of a smooth muscle cell is more complex. First, the smooth muscle cell typically receives input from many different kinds of nerve fibers. The various cell membrane receptors in turn activate different intracellular signal-transduction pathways which may affect (a) membrane channels, and hence, electrical activity (b) calcium storage or release or (c) the proteins of the contractile machinery. While each have their own biochemically specific ways, the actual mechanisms are for the most part known only in outline. 

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