Cytokine receptors and signal transduction

Rubinstein, M. et al., Recent advances in cytokines, cytokine receptors and signal transduction, Cytokine Growth Factor Rev., 9, 175, 1998. 

Miyajima A, Kitamura T, Harda N, Yokota T, et al. 1992. Cytokine receptors and signal transduction. Ann Rev Immunol. 10 295-331. 

Taga, T., and Kishimoto, T. (1992). Cytokine receptors and signal transduction. FASEB J. 6, 3387-3396. 

Miyajima, A., Kitamura, T, Harada, N. et al. (1992) Cytokine receptors and Signal Transduction. Annual Reviews of Immunology, 10, 295-331 Review of function and methods of stimulation. 

IL-4 acts its biological effects by binding to the IL-4 receptor (IL-4R) [119(NC)]. The IL-4R is composed of two subunits an a subunit required for IL-4 binding and signal transduction, and a y subunit common to several cytokine receptors [120(111)]. The IL-4R a chain consists of one extracellular domain, that contains the IL-4 binding site, and a large cytoplasmic domain. 

We turn now to a second important class of cell-surface receptors, the cytokine receptors, whose cytosolic domains are closely associated with a member of a family of cytosolic protein tyrosine kinases, the JAK kinases. A third class of receptors, the receptor tyrosine kinases (RTKs), contain intrinsic protein tyrosine kinase activity in their cytosolic domains. The mechanisms by which cytokine receptors and receptor tyrosine kinases become activated by ligands are very similar, and there is considerable overlap in the intracellular signal-transduction pathways triggered by activation of receptors in both classes. In this section, we first describe some similarities in signaling from these two receptor classes. We then discuss the JAK-STAT pathway, which is initiated mainly by activation of cytokine receptors. 

Certain phosphotyrosine residues formed in activated cytokine receptors and RTKs serve as binding, or docking, sites for SH2 domains or PTB domains, which are present in a large array of Intracellular signal-transduction proteins. 

Once they are bound to an activated receptor, some signal-transduction proteins are phosphorylated by the receptor s intrinsic or associated kinase to achieve their active form. Binding of other signal-transduction proteins, present in the cytosol in unstimulated cells, positions them near their substrates localized in the plasma membrane. Both mechanisms can trigger downstream signaling. Several cytokine receptors (e.g., the IL-4 receptor) and RTKs (e.g., the insulin receptor)... 

In previous sections, we have seen how signal transduction from cytokine receptors and receptor tyrosine kinases (RTKs) begins with formation of multiprotein complexes associated with the plasma membrane. Here we discuss how these receptors initiate signaling pathways that Involve membrane-bound phosphorylated inositol lipids, collectively referred to as phosphoinositides. We begin with the branch of the phospholnositide pathway that also is mediated by G protein-coupled receptors and then consider another branch that is not shared with these receptors. 

In previous sections we discussed several signal-transduction pathways activated immediately after stimulation of cytokine receptors and receptor tyrosine kinases (RTKs). If the level of hormone in the environment remains high for several hours, cells usually undergo desensitization, such that they no longer respond to that concentration of hormone. This prevents inappropriate prolonged receptor activity, but under these conditions cells usually will respond if the hormone level is Increased further. Tlgand-dependent receptor-mediated endocytosis, which reduces the number of available cell-surface receptors, is a principal way that cells are desensitized to many peptides and other hormones. 

Melendez, A.J., and Ibrahim, F.B., Antisense knockdown of sphingosine kinase 1 in human macrophages inhibits C5a receptor-dependent signal transduction, Ca2 + signals, enzyme release, cytokine production, and chemotaxis, J Immunol, 173 (2004) 1596-1603. 

Daun JM, Fenton MJ. Interleukin-1/Toll receptor family members receptor structure and signal transduction pathways. J Interferon Cytokine Res 2000 20 843-855. 

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