The Structural and Functional Basis of Cytokine Receptor Activation : Lessons From the Common b Subunit of the Granulocyte - Macrophage Colony - Stimulating Factor , Interleukin - 3 ( IL - 3 ) , and IL - 5 Receptors

C ily. However, it is becoming clear that within this superfamily, structurally similar subfamilies exist whereby some reYTOKINE RECEPTORS are cell-surface glycoproteins that bind specifically to cytokines and transduce their signals. These receptors enable cells to communicate with ceptors or receptor subunits are more related to each other than to other members of the receptor superfamily. For exthe extracellular environment by responding to signals generated in the vicinity or in other parts of the organism. Thus, ample the recently cloned receptor for TPO (TPOR) is more closely related to the EPO receptor (EPOR) and bc than to the initial binding of cytokines to their receptors is a key event that occurs rapidly, at very low cytokine concentraother cytokine receptors. In functional terms some receptors have subunits that subtions, is usually virtually irreversible, and leads to intracellular changes resulting in a biologic response. The biologic serve similar functions. For example, the common b subunit (bc ) shared by the GM-CSF, IL-3, and IL-5 receptors is response can vary between cytokine receptors and from cell to cell but in general it involves gene expression, changes functionally analogous to gp130, which is the common subunit of the IL-6, CNTF, cardiotrophin, oncostatin M, LIF, in the cell cycle, and release of mediators such as cytokines themselves. and IL-11 receptors, to IL-2Rg which is shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, and to the common Cytokine receptors function as oligomeric complexes consisting of typically two to four receptor chains that may be subunit of the IL-4 and IL-13 receptors. These common subunits have the dual function of affinity-converting the the same or different. In single subunit receptors the subunits fulfill the dual role of binding to cytokines and signaling. initial cytokine binding into a high-affinity state, and of being the major signal transducer in each of these receptor systems. Examples of receptors that use a single type of subunit are those for growth hormone (GH), erythropoietin (EPO), granThe communal nature of these subunits helps explain much of the overlapping activities of the different cytokines in ulocyte colony-stimulating factor (G-CSF), and thrombopoietin (TPO). In multi-subunit receptors the different each receptor system. This review focuses mostly on these communal subunits subunits may perform specialized functions such as ligandbinding or signal transduction. Multi-subunit receptors may and, in particular, on the structure of the common b subunit (bc ) of the human GM-CSF, IL-3, and IL-5 receptors and consist of two subunit types such as the receptors for granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), the mechanism of activation of this receptor family. This review does not address the activation pathways and signaland IL-5 where an a subunit is specific for each ligand and a b subunit is common to all three (bc ), with both chains ing molecules associated with bc following receptor activaparticipating in signaling. The IL-6 receptor also contains two subunit types, IL-6Ra and gp130. However, in this case the function of each chain is more exclusive, with IL-6Ra From the Department of Immunology, Hanson Centre for Cancer Research, the Institute of Medical and Veterinary Science, Adelaide, being the major binding protein with no direct role in signalAustralia. ing, and gp130 being the signal transducer. Receptors that Submitted August 15, 1996; accepted October 22, 1996. contain three different subunits are the CNTF receptor Supported by grants from the National Health and Medical Re(CNTFR), formed by the CNTFRa chain, gp130, and the search Council of Australia and the Anti-Cancer Foundation of the leukemia inhibitory factor (LIF) receptor, and the IL-2 reUniversities of South Australia. C.J.B. is a Rotary Peter Nelson ceptor (IL-2R) which consists of the IL-2Ra chain or tac Leukaemia Research Fellow of the Anti-Cancer Foundation of the (which is not a typical member of the cytokine receptor Universities of South Australia. family), IL-2Rb, and IL-2Rg, with the latter two being the Address reprint requests to Angel F. Lopez, MD, PhD, Hanson signaling molecules. Centre for Cancer Research, the Institute of Medical and Veterinary The cloning of cytokine receptors has shown a striking Science, Frome Rd, Adelaide 5000, Australia. structural and functional conservation which has justified q 1997 by The American Society of Hematology. 0006-4971/97/8905-0039$3.00/0 their distinct grouping into the cytokine receptor superfam-