The evolution of haematopoietic cytokine/receptor complexes

The evolutionary expansion of the haematopoietic cytokines and their receptors is characterized by the duplication of both cytokines and receptors. A systematic analysis of primary sequence homology indicates that receptors for gp130-associated cytokines group into signal transducing and non-signal transducing receptors. This observation is consistent with the evolution of the interleukins 6, 11 and 12, granulocyte colony stimulating factor (G-CSF), leukemia inhibitory factor (LIF), oncostatin M, and the ciliary neurotrophic factor complexes from a common ancestral complex which included a homodimer of gp130-like signalling receptors and an interleukin 6 receptor-like non-signalling receptor. Alterations in the components of the complex are proposed to have arisen by receptor duplication and divergence to allow signal transduction via a LIF receptor/gp130 heterodimer, and loss of the non-signalling receptor component in the G-CSF and the LIF lineage. The short-chain haematopoietins and their receptors do not group clearly, although interleukins 4 and 13 grouped together, as did 2 and 10. Internal duplication of the ligand-binding domain appears to have occurred independently in three separate lineages. These observations have implications for the classification of cytokines and receptors, and for the modelling by homology of their structures and interactions.