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. Highaffinity 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.

A role for extracellular matrix binding receptors in regulating hematopoietic growth factor signaling

“…N eutrophils and mononuclear phagocytes migrate from blood vessels to various tissue sites after exposure to a variety of stimuli, including antigens, bacterial products, cytokines, and oxidized low-density lipoproteins (1,2). The ability of these cells to traverse the endothelium and become activated at only specific sites of tissue injury is critical for modulating the host inflammatory response.…”

“…One of the most important cytokines involved in the regulation of the host defense is the human granulocyte-macrophage colony-stimulating factor (GM-CSF), which is produced by activated T cells, macrophages, endothelial cells, and fibroblasts (1,2). GM-CSF initiates its function by binding to its heterodimeric receptor present on myeloid progenitors and mature monocytes, neutrophils, eosinophils, basophils, and dendritic cells (3)(4)(5)(6).…”

“…The isolated ␣ receptor binds to GM-CSF with low affinity and forms a complex with the ␤ receptor to create the high affinity receptor. Evidence suggests that the GM-CSF receptor exists as an ␣ 2 ␤ 2 tetrameric complex in the ligand-bound state although the role of a simple ␣␤ complex cannot be ruled out (1). The organization of the GM-CSF receptor is similar to the receptors for two other hematopoietic growth factors, IL-3 and IL-5 (5, 6).…”

“…Neither the GM-CSF receptor nor other members of the cytokine receptor superfamily possess intrinsic enzymatic activity to mediate their intracellular signaling (1,13). The organization of these receptors includes extracellular domains characterized by 200-aa modules containing two fibronectin-like beta barrel structures, a single transmembrane domain, and an intracellular domain (15).…”

“…The ␣ subunit consists of a cytoplasmic domain of limited size, whereas the ␤ subunit consists of a more extensive intracellular domain with multiple tyrosine residues that are targets for phosphorylation by tyrosine kinases including Janus kinase (JAK), to result in the recruitment of Src homology 2 (SH2)-containing proteins to this receptor subunit (14). After ligand binding and the assembly of the high affinity GM-CSF receptor, tyrosine kinases such as JAK2 are recruited to the intracellular domain of the ␤ receptor to activate the JAK͞signal transducer and activator of transcription (STAT), ras͞mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3-kinase) pathways, leading to increases in the proliferation, maturation, survival, and activation of myeloid and monocyte lineages (1,(7)(8)(9)13). Because a subset of GM-CSF receptors preexists as heterodimers in the absence of ligand binding (14), mechanisms are likely opera- tive that prevent the activation of this receptor in the absence of tissue injury.…”