Mechanism of Activation of the GM‐CSF, IL‐3, and IL‐5 Family of Receptors

Abstract

The process of ligand binding leading to receptor activation is an ordered and sequential one. High‐affinity binding of GM‐CSF, interleukin 3 (IL‐3), and IL‐5 to their receptors induces a number of key events at the cell surface and within the cytoplasm that are necessary for receptor activation. These include receptor oligomerization, activation of tyrosine kinase activity, phosphorylation of the receptor, and the recruitment of SH2 (src‐homology) and PTB (phosphotyrosine binding) domain proteins to the receptor. Such a sequence of events represents a recurrent theme among cytokine, growth factor, and hormone receptors; however, a number of very recent and interesting findings have identified unique features in this receptor system in terms of: A) how GM‐CSF/IL‐3/IL‐5 bind, oligomerize, and activate their cognate receptors; B) how multiple biological responses such as proliferation, survival, and differentiation can be transduced from activated GM‐CSF, IL‐3, or IL‐5 receptors, and C) how the presence of novel phosphotyrosine‐independent signaling motifs within a specific cytoplasmic domain of β_C may be important for mediating survival and differentiation by these cytokines. This review does not attempt to be all‐encompassing but rather to focus on the most recent and significant discoveries that distinguish the GM‐CSF/IL‐3/IL‐5 receptor subfamily from other cytokine receptors.