Cytokine responses and signal transduction

The responses of haemopoietic cells to cytokines include survival, proliferation, differentiation and stimulation of mature cell function. Once cytokines have bound to their receptors on the cell surface, they activate signal transduction pathways that transmit the signal to the nucleus and ultimately stimulate the transcription of regulatory genes. Haemopoietic progenitors require multiple cytokines for their optimal growth and development (Table 1.2). These growth factors act in concert to coordinate the various cellular functions that are necessary for the cell division and progressive differentiation required for the formation of mature functioning end cells. There are many examples of cytokines acting in synergy when the outcome is greater than expected from the sum of the individual cytokines acting alone. Also, cytokines are pleiotropic in their actions, and several cytokines are known to share the same functions. This level of complexity is very difficult to rationalize, but it is becoming apparent that intracellular coordination is achieved by co-localization of sequentially acting signalling proteins, or by binding interactions with adaptor complexes, cytoskeletal structures or molecular targets, for the selective activation of downstream targets. Outside the cell, haemopoietic cell responses may be modulated by controlled access of cytokines to target cell receptors, as discussed below.

Many haemopoietic growth factor and cytokine receptors belong to the haematopoietin receptor superfamily (Figure 1.7). These are type 1 transmembrane glycoproteins with modular extracellular domains. All members dimerize when they bind their ligand. G-CSF and erythropoietin (Epo) receptors homo-dimerize, whereas the P-chains of the interleukin (IL) 3, IL-5 and GM-CSF receptors dimerize with a common beta (Pc) chain to form a high-affinity receptor. Other members of the haematopoietin receptor superfamily (IL-6, IL-11, IL-12 and leukaemia inhibitory factor, LIF) require the presence of a transmembrane protein, gp130, to transduce a signal.

A separate group of receptors has intrinsic tyrosine kinase activity and contains receptors for SCF, hepatocyte growth factor (HGF) and Flt3 ligand (FL). It is evident that cytokine receptor systems not only act in a linear-independent manner, but also influence the activity of other cell-surface receptor systems. Biochemical studies have revealed interactions between haemopoietic cytokine receptors, including interactions of Pc with Epo and G-CSF receptors. However, it is not established

Lewis Structure
Figure 1.7 Representation of the modular structures of the haematopoietin receptor superfamily, exemplified by the receptors for GM-CSF and G-CSF (after Lewis and Gordon, 2003).

that these biochemically documented phenomena, such as receptor transmodulation, transphosphorylation and physical interaction, are biologically significant.

Cytokines regulate a variety of haemopoietic cell functions through the activation of multiple signal transduction pathways (Figure 1.8). The major pathways relevant to cell proliferation and differentiation are the Janus kinase (Jak)/signal transducers and activators of transcription (STATs), the mitogen-activated protein (MAP) kinase and the phosphatidylinositol (PI) 3-kinase pathways. Jaks function upstream of STATs, which are activated by phosphorylation, and then dimerize and migrate to the nucleus, where they bind to specific DNA motifs. Thus, the Jak-STAT pathway represents the most direct pathway for transmitting a signal from the cytokine receptor to DNA. Ras regulates the best-characterized MAPK cascade, which consists of Raf isoforms MEK1/2 and ERK1/2 and controls proliferation. PI3 kinases phosphorylate inositol lipids, which, in turn, activate downstream targets (Akt, Erk, p70s6k, vav-rac) and influence many different cellular processes. These include cell survival, cell cycle progression, proliferation and reorganization of the actin cytoskeleton. The Jak-STAT pathway is implicated in IL-3, IL-6, Epo and G-CSF signalling, the MAP kinase pathway in Epo, GM-CSF, G-CSF and IL-3 signalling, and the PI3 kinase pathway in IL-6, Epo, GM-CSF, G-CSF and M-CSF signalling.

Thus, all of the haemopoietic growth factors appear to be capable of activating all of the major signal transduction pathways simultaneously. The several pathways that have been identified and the multiple responses, pleiotropism and redundancy that are well-known features of haemopoietic cytokines raise the possibility that a particular cytokine may have different effects in different cell types and possibly utilize different signal transduction pathways for specific functions. Moreover, combinations of cytokines may cooperate to activate further signal transduction pathways that are not activated when cytokines are used individually. Such interactions among receptor-mediated signals provide a mechanism for merging the activities of different ligand-receptor systems and achieving novel cellular outcomes.

Figure 1.8 Generalized diagram of the signal transduction pathways activated by cytokines and their receptors in haemopoietic cells.

Figure 1.8 Generalized diagram of the signal transduction pathways activated by cytokines and their receptors in haemopoietic cells.

Cytokine Induced Signal Transduction

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