Cytokine Receptor Signaling
2010; Elsevier BV; Linguagem: Inglês
10.1016/b978-0-12-374145-5.00063-2
AutoresMojib Javadi Javed, Terri D. Richmond, Dwayne L. Barber,
Tópico(s)Immune Cell Function and Interaction
ResumoThe focus of this chapter is to summarize signaling pathways activated by cytokine receptors and developmental regulation of the cytokine signaling pathway and the involvement of this pathway in human disease using the Erythropoietin Receptor (EPO-R) as a model. Cytokines regulate many steps of proliferation, cell survival, and differentiation within the bone marrow and extrahematopoietic tissues. These growth factors generally fall into a superfamily of helical proteins that contain four α-helices that possess a unique up–up–down–down architecture. Cytokines exert their function by binding to cognate receptors that are expressed in the appropriate target cell. Receptors are activated when a high-affinity ligand–receptor complex is generated. Analysis of the unliganded extracellular domain of the EPO-R revealed that this region of the receptor exists as a preformed dimmer. Comparison with the structure of the EPO-R extracellular domain with bound EPO revealed that the D1 domains are 120° apart, whereas the D2 domains are parallel to each other. This reduces the spacing between the D2 domains to 30 Å. It is believed that this conformational change is adequate to bring the associate Janus tyrosine kinase 2 (JAK2) proteins in close proximity to facilitate activation. Once receptor-JAK kinase complexes are activated, JAK kinases tyrosine phosphorylates the cytoplasmic tail of cytokine receptors. Since cytokines regulate many of the steps in proliferation, differentiation, and survival of hematopoietic cells, it is reasonable to assume that the cytokine signaling pathway may be a target for gain or loss-of-function mutations.
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