Stem Cell Factor (SCF)- The c-kit ligand

Hematopoiesis is governed by a number of cytokines that promote the survival, proliferation, and differentiation of hematopoietic stem cells and progenitor cells. Stem cell factor (SCF; also known as kit ligand, mast cell growth factor, or steel factor) is a hematopoietic cytokine that triggers its biologic effects by binding to its receptor, c-kit.
It is a glycoprotein that plays a key role in hematopoiesis acting both as a positive and negative regulator, often in synergy with other cytokines. The concentration of SCF in normal human serum is, on average, 3.3 ng/mL.

SCF is a member of the helical cytokine structural superfamily characterized by a double-crossover four-helix bundle topology. It is normally found in both soluble and transmembrane forms. Soluble SCF exists as a non-covalently associated homodimer is glycosylated, and has considerable secondary structure, including regions of alpha helices and beta sheets. Each SCF monomer contains two intra-chain disulfide bridges, Cys4–Cys89 and Cys43–Cys138. The N-terminal 141 residues of SCF have been identified as a functional core, SCF1–141, which includes the dimer interface and portions that bind and activate the receptor Kit. The human SCF gene has been mapped to chromosome 12q22-12q24. SCF is produced by various fibroblast-type cells including bone marrow stromal cells.

SCF transduces signals by ligand mediated dimerization of its receptor, Kit, which is a type III receptor protein-tyrosine kinase related to the receptors for platelet-derived growth factor (PDGF), macrophage colony-stimulating factor, Flt-3 ligand and vascular endothelial growth factor (VEGF). The class III receptors are characterized by the presence of five immunoglobulin-like domains in their extracellular portion. SCF binds to the second and third immunoglobulin domains while the fourth domain plays a role in receptor dimerization. Binding of SCF to Kit leads to receptor dimerization and activation of protein kinase activity. The receptor becomes autophosphorylated at tyrosine residues during activation; the resulting phosphotyrosine residues serve as docking sites for signal transduction molecules containing SH2 and phosphotyrosine-binding (PTB) domains. Activated Kit also catalyzes the phosphorylation of substrate proteins.

SCF is of particular importance in the mast cell and erythroid lineages, but also acts on multipotential stem and progenitor cells, megakaryocytes, and a subset of lymphoid progenitors. It also plays a key role in mast cell development, gametogenesis, and melanogenesis. The role of SCF also includes to change the BFU-E(burst-forming unit-erythroid) cells, which are the earliest erythrocyte precursors in the erythrocytic series, into the CFU-E (colony-forming unit-erythroid). SCF, along with bFGF (basic fibroblast growth factor) and LIF (lymphocyte inhibitory factor), prevents spontaneous differentiation of primitive embryonic stem cells in cell culture.

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