Subfamilies of Class I Cytokine Receptors Have Signaling Subunits in Common

Several subfamilies of class I cytokine receptors have been identified, with all the receptors in a subfamily having an identical signal-transducing subunit. Figure 12-7 schematically illustrates the members of three receptor subfamilies, named after GM-CSF, IL-2, and IL-6.

The sharing of signal-transducing subunits among receptors explains the redundancy and antagonism exhibited by some cytokines. Consider the GM-CSF receptor subfamily, which includes the receptors for IL-3, IL-5, and GM-CSF (see Figure 12-7a). Each of these cytokines binds to a unique low-affinity, cytokine-specific receptor consisting of an a subunit only. All three low-affinity subunits can associate noncova-lently with a common signal-transducing p subunit. The resulting dimeric receptor not only exhibits increased affinity for the cytokine but also can transduce a signal across the membrane after binding the cytokine (Figure 12-8a). Interestingly, IL-3, IL-5, and GM-CSF exhibit considerable redundancy. IL-3 and GM-CSF both act upon hematopoietic stem cells and progenitor cells, activate monocytes, and induce megakaryocyte differentiation. All three of these cytokines induce eosinophil proliferation and basophil degranulation with release of histamine.

Since the receptors for IL-3, IL-5, and GM-CSF share a common signal-transducing p subunit, each of these cyto-kines would be expected to transduce a similar activation signal, accounting for the redundancy among their biological effects (Figure 12-8b). In fact, all three cytokines induce the same patterns of protein phosphorylation. Furthermore, IL-3 and GM-CSF exhibit antagonism; IL-3 binding has been shown to be inhibited by GM-CSF, and conversely, binding

FIGURE 12-7

Schematic diagrams of the three subfamilies of class I cytokine receptors. All members of a subfamily have a common signal-transducing subunit (blue), but a unique cytokine-specific subunit. In addition to the conserved cysteines (double black lines) and WSXWS motifs (red lines) that characterize class I cytokine receptors, immu-noglobulin-like domains are present in some of these receptors. CNTF = ciliary neurotrophic factor; LIF/OSM = leukemia-inhibitory factor/ oncostatin. [Adapted from K. Sugamura et al, 1996, Annu. Rev. Immunol. 14:179.]

(a) GM-CSF receptor subfamily (common P subunit) GM-CSF IL-3 IL-5

GM-CSFRa

IL-3R

IL-5R

(b) IL-6 Receptor subfamily (common gp130 subunit)

CNTF LIF/OSM

IL-6

IL-11

CNTFR

gp130 gp130 gp130

gp130

(c) IL-2 receptor subfamily (common y subunit)

IL-2Ra

IL-2Ra

IL-15Ra

IL-15Ra

IL-2RP IL-2RP IL-7R IL-9R

IL-4R

of GM-CSF has been shown to be inhibited by IL-3. Since the signal-transducing p subunit is shared between the receptors for these two cytokines, their antagonism is due to competition for a limited number of p subunits by the cytokine-specific a subunits of the receptors (Figure 12-8c).

A similar situation is found among the IL-6 receptor subfamily, which includes the receptors for IL-6, IL-11, leukemia-inhibitory factor (LIF), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF) (see Figure 12-7b). In this case, a common signal-transducing subunit called gp130 associates with one or two different cytokine-specific subunits. LIF and OSM, which must share certain structural features, both bind to the same a subunit. As expected, the cytokines that bind to receptors in this subfamily display overlapping biological activities: IL-6, OSM, and LIF induce synthesis of acute-phase proteins by liver hepatocytes and differentiation of myeloid leukemia cells into macrophages; IL-6, LIF, and CNTF affect neuronal development, and IL-6, IL-11, and OSM stimulate megakaryocyte maturation and platelet production. The presence of gp130 in all receptors of the IL-6 subfamily explains their common signaling pathways as well as the binding competition for limited gp130 molecules that is observed among these cytokines.

A third signal-transducing subunit defines the IL-2 receptor subfamily, which includes receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 (see Figure 12-7c). The IL-2 and the IL-15 receptors are heterotrimers, consisting of a cytokine-specific a chain and two chains—p and y—responsible for signal transduction. The IL-2 receptor y chain functions as the signal-transducing subunit in the other receptors in this subfamily, which are all dimers. Recently, it has been shown that congenital X-linked severe combined immunodeficiency (XSCID) results from a defect in the y-chain gene, which maps to the X chromosome. The immunodeficiencies observed in this disorder are due to the loss of all the cytokine functions mediated by the IL-2 subfamily receptors.

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