The PDGFR receptor family

CSF-1R Colony-stimulating factor-1 (CSF-1) receptor (CSF-1R) is the major regulator of tissue macrophages and, with RANKL, controls osteoclast development. The CSF-1R also regulates the development of Paneth and Langerhans cells, neuronal progenitor differentiation, and functions of cells of the female reproductive tract. CSF-1R is the only class III RTK known to be activated by two ligands of unrelated primary sequence, CSF-1, and interleukin-34 (IL-34). However, IL-34 and CSF-1 resemble each other in their three-dimensional structure, compete with each other for binding to the CSF-1R, and are similarly able to support myeloid lineage differentiation in vitro. Nevertheless, they differ in their spatiotemporal expression patterns, developmental roles, mechanism of interaction with the CSF-1R, signal activation kinetics, and strength. CSF-1 signals exclusively through the CSF-1R, while IL-34 interacts with an additional receptor, the receptor protein-tyrosine phosphatase-ζ (RPTP-ζ) which is co-expressed with the CSF-1R in the hematopoietic stem and neural progenitor cells, but not in macrophages. Inappropriate overexpression of the CSF-1R and autocrine CSF-1 regulation contribute to the development of acute leukemias and Hodgkin’s lymphoma. CSF-1-regulated tumor-associated macrophages enhance tumor progression and metastasis. Dominant inactivating point mutations in the CSF-1R kinase domain cause a late-onset leukoencephalopathy leading to progressive cognitive dysfunction and dementia. Because studies in mice indicate that the CSF-1R plays an important role in cancer progression and in inflammatory diseases involving macrophages and/or osteoclasts, the CSF-1R is a therapeutic target in several diseases. Conversely, CSF-1R activation may be appropriate in the treatment of certain neurodegenerative diseases, bone fractures, and female infertility. FLT3 Fms-like tyrosine kinase 3 (FLT3) is expressed in the hematopoietic system where it directly regulates the proliferation and differentiation of dendritic cells (DC), B-cell progenitors, and myelomonocytic cells. It is also expressed in placenta, gonads, and brain, where its functions have not been reported. Active, dimeric FLT3 ligand (FL) is primarily expressed as a cell-surface, membrane-spanning glycoprotein that is released by proteolytic cleavage. Alternative splicing generates two other isoforms, one secreted and the other stably expressed at the cell surface. FLT3–FL dimer interaction involves the FLT3 extracellular domains D2 and D3 only, with D3 contributing almost exclusively to the ligand-binding epitope. Unique aspects of this interaction include a small receptor–ligand interface, ligand–receptor-binding preceding receptor dimerization, and a large D1 domain of distinctive plasticity. Kinase autoinhibition by the intracellular juxtamembrane domain is relieved by ligand-induced juxtamembrane tyrosine phosphorylation. The major documented FLT3 signaling pathways are the MAPK/ERK and PI3K/AKT pathways and the downstream mTOR and NF-κB pathways. FLT3-activating mutations have been identified in ~40 % of acute myeloid leukemia patients, most commonly as in-frame internal tandem duplications in the juxtamembrane domain that are associated with increased STAT5 phosphorylation and activation of STAT5 targets. Small molecule FLT3 inhibitors target FLT3 kinase function, biogenesis, or stability. Despite the effectiveness of the kinase inhibitors against the constitutively activated mutant FLT3 receptors, it is likely that they will need to be used in combination with other therapeutic modalities. The KIT Receptor Tyrosine Kinase Stem cell factor (SCF) is a dimeric ligand that mediates its effects on cells by binding to the receptor tyrosine kinase KIT leading to its dimerization and activation. This leads to autophosphorylation of KIT and initiation of downstream signal transduction. Proteins involved in transducing the signal into the cells are recruited to activate KIT through specific interaction domains (e.g., SH2 and PTB domains) that specifically bind to phosphorylated tyrosine residues in the intracellular region of KIT. KIT-induced signaling is known to mediate cell survival, migration, and proliferation depending on the cell type. Mice with loss-of-function mutations in either the KIT locus or the KITLG locus, encoding the KIT ligand SCF, have demonstrated the importance of KIT for normal hematopoiesis, pigmentation, fertility, gut motility, and some aspects of the nervous system. Deregulated KIT kinase activity has been found in a number of pathological conditions, including cancer and leukemia. Loss-of-function mutations in KIT have been observed and shown to give rise to a condition called piebaldism in humans, resulting in a partial loss of pigmentation. This review provides a summary of our current knowledge regarding structural and functional aspects of KIT signaling both under normal and pathological conditions.