Cytokines and Cytokine Receptors Regulating Cell Survival, Proliferation, and Differentiation in Hematopoiesis

This chapter gives an overview on adult hematopoiesis, with an emphasis on the cytokines and their target signaling pathways that are important in steady-state maintenance of non-lymphoid cell lineages. The three hematopoietic cytokines signaling through tyrosine kinase receptors, stem cell factor (SCF), Flt3 ligand (FL), and colony stimulating factor-1 (CSF-1), are members of a family of homodimeric cytokines that share some sequence and structural similarity. The SCF, CSF-1, and FL receptors, all members of the PDGF receptor family, possess an extracellular domain (ECD) composed of five heavily glycosylated immunoglobulin-like repeats, a transmembrane domain, and an intracellular tyrosine kinase domain that is interrupted by a kinase insert domain. The receptor phosphotyrosines create binding sites for src homology region 2 (SH2) and other phosphotyrosine binding domains of signaling and adaptor proteins that bind the receptor and may themselves become tyrosine phosphorylated. SCF influences development in the three different lineages involving pigmentation, hematopoiesis, and fertility. Both secreted and cell surface forms are widely expressed during embryogenesis and in a variety of adult tissues, including bone marrow stromal cells, fibroblasts, and endothelial cells, as well as yolk sac and placenta. Erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), and thrombopoietin (TPO) signal by initiating homodimerization of their cognate non-tyrosine kinase receptors, although additional receptor subunits may be involved. These receptors belong to a large family of receptors, the cytokine receptor family, defined by the presence of an ECD cytokine receptor module. These modules contain conserved short amino acid sequence elements, particularly two pairs of conserved cysteine residues near the amino terminal end of the motif and a Trp-Ser-X-Trp-Ser (WSXWS) sequence near the transmembrane domain.