TCR, BCR, Soluble Tyrosine Kinases and NFAT

Table 17.2  Diversity in cytokine-induced signalling: The spectrum of downstream STATs and STAT-associated proteins determine the outcome of the cellular response to a particular member of the interferon family. A thick red arrow represents the predominant pathway, thin blue arrows signify alternative pathways.

Information from Takaoka and Yanai.31 Adapted from Ihle.41

Down-regulation of the JAK-STAT pathway

Nuclear dephosphorylation and recycling of STATs

Dimerized and phosphorylated STATs are rapidly dephosphorylated in the nucleus.44 This is thought to be caused by interactions that force a rearrangement of the dimer partners, so breaking the SH2 domain phosphotyrosine links. This exposes the phosphotyrosines to nuclear

phosphatases (Figure 17.10).45 The enzymes involved are not clearly established. In order to maintain the system of signalling, the dephosphorylated STATs exit the nucleus to be re-phosphorylated at the membrane and return as active dimers. When large numbers of cytokine receptors are active, the STAT proteins recirculate rapidly and in consequence, a large proportion is retained as active dimers in the nucleus, stimulating gene transcription. When only few receptors are active, the majority accumulate in the cytoplasm in their inactive state. STAT proteins appear to act as a remote sensors, communicating between the cell surface and the nucleus, though, as described below, the situation is actually more complex.46

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Signal Transduction

Fig 17.10  STAT proteins act as remote sensors.

STAT proteins that dissociate from the DNA are dephosphorylated by tyrosine phosphatases (1). They return to the cytoplasm and only re-enter the nucleus if they are rephosphorylated by (active) IFN receptors (2). With a large proportion of receptors occupied, the cycle is rapid and STAT accumulates in the nucleus. With few receptors occupied, the cycle is slow, resulting in an accumulation of STAT in the cytoplasm. Effectively, STAT acts as a remote sensor of receptor occupation.

Dephosphorylation of the IFN- receptor-1

The dual specificity phosphatases SHP-1 and SHP-2 (see page 653) bind phosphorylated IFNΑR1, thereby competing with and dephosphorylating STAT and the tyrosine kinases. The pathway is effectively silenced

(Figure 17.11a). SHP-1 is mainly expressed in haematopoietic cells, SHP-2 ubiquitously. SHP-2 may also act in the nucleus and participate in the dephosphorylation of nuclear STATs.47 Loss of SHP-1 results in hyperphosphorylation of JAK1 and is the cause of immunological and

haematopoietic dysfunctions (mice exhibit the ‘motheaten’ phenotype48). Lack of SHP-2 is embryonic lethal. CD45 is also involved, since its absence also causes hyperactivation of JAK1. Other cytosolic phosphatases, PTP1B and T Cell-PTP, have the capacity to dephosphorylate both

JAK2 and TYK2. This results in reduced phosphorylation of IFNAR1 and thus an arrest of STAT signalling (Figure 17.11b). This subject is further considered in Chapter 21.

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TCR, BCR, Soluble Tyrosine Kinases and NFAT

Fig 17.11  Inactivation of the IFN pathway.

Down-regulation of the IFN pathway occurs at different levels. (a) Tyrosine phosphatase SHP-1 binds the phosphorylated IFNAR1 receptor, so preventing association of STAT2. It dephosphorylates and de-activates STAT1/2 complexes and also the tyrosine protein kinases associated with the IFN receptors.

(b) PTP1B deactivates TYK2 and JAK1, so preventing further activation of STATs-1 and -2. (c) The SH2 domain of SOCS recognizes tyrosine-phosphorylated IFNAR1 and JAK1. Binding prevents further access of STAT2 to the receptor and inhibits JAK1 activity. SOCS proteins associate with components of a big E3-ligase complex causing polyubiquitylation (K48) of IFNAR1, JAK1 and STAT proteins. Polyubiquitylated proteins are destroyed by the proteasome.

(d) PIAS proteins associate with STAT1/2 and IRF-9 and prevent their association with DNA.

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