Intracellular signal transduction cytokines

Endocytosis / Phagocytosis Active Transport Cellular Proliferation Intracellular Cytokine Production Intracellular Signal Transduction Intracellular Free Ions (e.g., Na, K, Ca)... 

This review will describe the biological functions and regulation of the recently identified cytokines—interleukins, chemokines, and peptide growth factors—their intracellular signal transduction and role in certain diseases, and different cytokine assay methods and their clinical applications. 

Thus, the IFN signaling model represents a paradigm for the functioning of many other cytokine receptors that utilize the JAK/STAT pathway for intracellular signal transduction (Ihle, 1996). The importance of individual members of the JAK kinase family and individual STAT proteins varies depending on the specific cytokine involved, but the basic principles remain the same. 

Second, some classes of receptors can initiate signaling via more than one intracellular signal-transduction pathway, leading to different cellular responses. This complication is typical of G protein-coupled receptors, receptor tyrosine kinases, and cytokine receptors. 

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. 

Fig. 15. Intracellular processes of activation of NFkB. The NFkB is present in latent form in the cytoplasm as a result of binding to the inhibitor protein IkB. Cytokine-induced signal transduction results in selective IkB phosphorylation, which is in turn ubiquitinated and degraded by the protea-some pathway. Free NFkB migrates to the mucleus by several localization signals. Binding of NFkB to its specific site of genes induces transcription of several NFKB-dependent genes. NFkB is then inactivated by newly synthesized IkB both in the cytoplasm and nucleus.

Some cytokine receptors can directly initiate signal transduction upon binding of ligand. In other cases additional elements are involved. For many receptors, the exact intracellular events triggered upon ligand binding remain to be elucidated. However, the molecular details of signal transduction pathways for others (e.g. the interferons) are now understood... 

The intracellular events triggered upon binding of type I or II interferons to their respective receptors are quite similar. The sequence of events, known as the JAK-STAT pathway, has been elucidated over the last few years. It has quickly become apparent that this pathway plays a prominent role in mediating signal transduction, not only for interferon, but also of many cytokines. 

The EPO receptor is a member of the haemopoietic cytokine receptor superfamily. Its intracellular domain displays no known catalytic activity, but it appears to couple directly to the JAK2 kinase (Chapter 8) that likely promotes the early events of EPO signal transduction. Other studies have implicated additional possible signalling mechanisms, including the involvement of G proteins, protein kinase C and Ca2+. The exact molecular events underlining EPO signal transduction remain to be elucidated in detail. 

Intracellular cytokine levels Surface marker expression Gene expression Protein expression Signal transduction... 

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