Fig. 2.

Structure of SCF/c-KIT proteins and downstream signalling pathways. Membrane-bound SCF (mSCF) contains an extracellular domain (red) that is responsible for recognizing and binding to c-KIT, a transmembrane domain (orange), and an intracellular domain (dark green). SCF also exists as a soluble protein (sSCF) secreted to the extracellular space. The five immunoglobulin-like domains (dark blue) in the extracellular domain of c-KIT are involved in ligand-binding and receptor dimerization. The transmembrane domain (violet) anchors c-KIT at the cytoplasm membrane and the intracellular region (green) is responsible for signal transduction. The receptor can be proteolytically cleaved and released from cell membrane, giving rise to a soluble c-KIT (s-KIT) consisting only of the extracellular domain. A truncated form of c-KIT (tr-KIT) residing at cytoplasm lacks the extracellular and transmembrane domains but retains part of the kinase domain. Binding of SCF homodimer to c-KIT induces receptor dimerization and auto-phosphorylation, and consequent activation of downstream signalling cascades. The cell survival PI3K/Akt pathway (dark blue) depends on the phosphorylation of p70 S6 kinase (p70S6K) via mammalian target of rapamycin (mTOR), which leads to increased expression of cyclin D3 and phosphorylation of retinoblastoma protein (Rb). SCF/c-KIT/PI3K/Akt signalling also contributes to cell survival by inactivation of the pro-apoptotic factor Bad. The Src pathway (pink) controls proliferation, cell-cycle progression, and migration by distinct actions of Akt, Fyn, and Lyn kinases. c-KIT activates PLC-γ (orange), that can also be activated by tr-KIT through SRC member Fyn, which induces cell proliferation. SCF/c-KIT signalling has also been linked with the activity of JAK/STAT pathway (purple) through the activation of JAK2 and consequent phosphorylation of STAT transcriptional regulators, which enhance proliferative activity. Activation of the MAPK pathway (light green) occurs upon binding of adaptor proteins, such as growth-factor receptor-bound protein-2 (Grb2) and guanine nucleotide exchange factor, son of sevenless (SOS), which determines the activation of the small G-protein RAS and the propagation of kinases signalling cascade