Cytokine receptor signaling

For many classes of cytokine receptors the first detectable intracellular signaling events are the tyrosine phosphorylation of proteins (Figure 1). This tyrosine kinase activity is either provided by the integral tyrosine kinase domains of the receptors, as for the PDGFR and EGFRs, or by the recruitment to the receptor of intracellular kinases. For example, the sre family of tyrosine kinases (lck, fyn, lyn, hck) are recruited by many members of the class I family, while the Janus tyrosine kinase family (Jak 1, Jak2, Jak3, Tyk2) are recruited by receptors of both the class I and the class II families. Tyrosine kinase activation appears to occur as a consequence of receptor homo- or hetero-oligomerization and is often accompanied by the phosphorylation of tyrosine residues in the intracellular domain of both the receptors and kinases themselves. The kinases in turn phosphorylate and activate other intracellular enzymes, such as phosphatidylinositol-3' kinase or PLCy. These enzymes are brought into the proximity of the tyrosine kinases by binding via their SH2 domains to the tyrosine phosphorylated receptors. Another class of proteins that binds to the phosphorylated receptors are the SH2 and PTB

1. Ligand binding

2. Receptor oltgomcrizalion

4. Receptor phosphorylation d>p

Monomeric G protein

Serine/threonine kinase cascades

Transcription factors

Monomeric G protein

Serine/threonine kinase cascades

Transcription factors

1. Ligand binding

2. Receptor oltgomcrizalion

5 Binding of Intracellular enzymes and adapter proteins

6- Activation of phosptiolipases and lipid kinases

Signaling lipids 1

Serine/threonine kinases

Transcription factors

Gene expression

5 Binding of Intracellular enzymes and adapter proteins

6- Activation of phosptiolipases and lipid kinases

Signaling lipids 1

Serine/threonine kinases

Transcription factors

Gene expression containing 'adapter' proteins such as She and Grh2, which in turn bind other cellular proteins (which may become kinase substrates) either by SH2 or SH3 interactions (SH3 domains bind proteins with pro-line-rich sequences). A third class of proteins that can interact with tyrosine phosphorylated receptors are the STAT (1-6) (signal transduction and activation of transcription) proteins. The STATs are substrates for the Janus kinases and homodimerize or hetero-dimerize on phosphorylation, after which they migrate to the nucleus and bind DNA. The STATs also require serine/threonine phosphorylation for transactivational activity.

The activation mechanism of the TNF receptor family and the IL-1R is less clear: as yet, no tyrosine kinases have been shown to associate with these receptors. The cytoplasmic domain of the TNF receptor has been shown to associate with several proteins termed TRAP (TNF receptor-associated protein), TRAF 1, 2 and 3 (TNF receptor-associated factor), TRADD (TNF receptor-associated death domain) and FAD (Fas-associated death domain). The functions of these proteins is still under investigation, although the TRAFs and TRADD and FAD are involved in NFkB activation and TNF-induced apotosis. The chemokine receptors signal via the activation of receptor-associated trimeric G proteins where both the a subunit and the (By complex can have functional activity. Distal targets include PLC|3 and adenylate cyclase, the activation of which leads to increases in intracellular calcium and cAMP.

Distal events in cytokine signaling generally involve the activation of small monomeric G proteins

Figure 1 Signaling mechanisms induced by tyrosine kinase, class I and class II cytokine receptors. P, Tyrosine phosphorylation: PTK, protein tyrosine kinase.

(e.g. p21ras), the production of signaling lipids such as diacylglycerol (DAG), phosphatidylinositol-3' phosphates and ceramide (by the action of sphingomyelinase). The effectors of the monomeric G proteins and the various lipids are a number of serine/threonine kinases such as those within the PKC family, c-raf and others. Many of these kinases are organized into cascades, leading to the activation of p42/44, p38 and p54 mitogen-activated protein kinases (MAPKs). The substrates for many of these kinases are transcription factors such as ATF-2, c-Fos, c-Jun and Elk-2 which are activated as a result of phosphorylation. Other key kinases involved in cytokine signaling are the p70S6K and IkB kinases (essential for the activation of NFkB). However, the mechanism leading to the activation of these kinases remains largely obscure. It is clear that cytokine receptors are involved in the parallel activation of multiple signaling pathways with different functional end-points. The full elucidation of the relationship between the activation of the various pathways to the different functions of a given cytokine is a future challenge.

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