br Conclusion CSF R may contribute to
Conclusion CSF-1R may contribute to limitation of targeted therapies by providing EGFR-bypassing signals that support proliferation. Multi-kinase inhibitors such as cabozantinib are available, and agents targeting CSF-1R are in clinical trials, however, at present, as inhibitors of tumor-associated macrophages . Taking into account the presence of CSF-1R in epithelial cancer Sodium Danshensu mg may improve combinatory therapeutic approaches to avoid resistance to targeted therapies. The following are the supplementary data related to this article.
Introduction Interleukin-34 (IL-34) was recently identified as the second functional ligand for colony stimulating factor (CSF)-1R (also known as cFMS) in a human monocyte proliferation screening assay (Lin et al., 2008). This discovery has long been foreshadowed by the more severe phenotype observed in CSF-1R null mice in comparison to that of CSF-1-deficient CSF-1op/CSF-1op mice (Dai et al., 2002). Like CSF-1 (also known as M-CSF), the better characterized ligand for CSF-1R, IL-34 stimulates phosphorylation of ERK1/2 in human monocytes and promotes the formation of the granulocyte-macrophage progenitor and megakaryocyte progenitor in human bone marrow cultures (Lin et al., 2008). Mediated by the common receptor CSF-1R, IL-34 and CSF-1 serve as the key regulators of the differentiation, proliferation, and survival of the mononuclear phagocyte lineage cells such as monocytes, macrophages, and osteoclasts (Droin and Solary, 2010). The function of IL-34 bears strong resemblance to that of CSF-1, but with several notable differences. Both cytokines support cell growth and survival in cell culture studies equivalently (Chihara et al., 2010, Wei et al., 2010). The IL-34 gene, when expressed under the control of the CSF-1 promoter, could rescue the phenotype of CSF-1op/CSF-1op mice (Wei et al., 2010). IL-34 can also substitute for CSF-1 to support RANKL-induced osteoclastogenesis (Baud'huin et al., 2010). However, IL-34 has been shown to induce a stronger but transient activation of CSF-1R and downstream effectors and rapidly downregulates CSF-1R expression (Chihara et al., 2010). Moreover, IL-34 and CSF-1 exhibit different spatiotemporal patterns of expression in both embryonic and adult tissues, which lead to complementary activation of CSF-1R (Wei et al., 2010). Most strikingly, IL-34 but not CSF-1 mRNA is detected together with CSF-1R in embryonic brain, which could explain why microglia develop in CSF-1-deficient but not CSF-1R-deficient mice (Ginhoux et al., 2010, Mizuno et al., 2011). Thus, while IL-34 and CSF-1 resemble each other, they are not necessarily identical in their developmental roles, biological activity, and signal activation kinetics or strength. Despite a lack of appreciable sequence similarity with other proteins, IL-34 was proposed by fold recognition to be a short-chain helical cytokine belonging to the same family as CSF-1, stem cell factor (SCF), and Flt3L (J.F.B., unpublished data; Garceau et al., 2010). These latter three dimeric hematopoietic cytokines functionally mimic the PDGF and VEGF cystine knot dimers, which are the activating ligands of the PDGFR subfamily of receptor tyrosine kinases (RTKs) (Savvides et al., 2000, Wiesmann and de Vos, 2000). All members of this RTK family share a similar overall architecture comprising multiple extracellular immunoglobulin (Ig)-like domains, a single transmembrane segment, and a cytoplasmic tyrosine kinase domain. Upon stimulation, CSF-1R dimerizes and autophosphorylates certain tyrosine residues in its intracellular domain, which recruits SH2-containing effector proteins and modulates macrophage differentiation (Pixley and Stanley, 2004). The structure of dimeric CSF-1 in complex with the first three Ig domains of CSF-1R reveals a nonsymmetrical 2:1 complex, in which one CSF-1 protomer approaches its receptor at the cleft between D2 and D3, while the second CSF-1 protomer remains unoccupied (Chen et al., 2008). This monovalent binding mode was recently reconciled as an assembly intermediate by a low resolution electron microscopy envelope of the complete CSF-1 ligand-receptor complex, which captured the anticipated bivalent assembly (Elegheert et al., 2011). In comparison to the extensively investigated CSF-1/CSF-1R molecular interaction, the structural basis whereby CSF-1R is also able to recognize IL-34, a distantly-related ligand with scant sequence identity, has remained elusive. IL-34 can function independently but does not synergize with CSF-1 (Lin et al., 2008). Indeed, CSF-1 competes with IL-34 for binding to CSF-1R (Wei et al., 2010), suggesting a common ligand-binding site on CSF-1R. In contrast, a recent bioinformatics analysis centered on the junction between D3 and D4 of CSF-1R as strongly conserved during evolution and suggested a unique binding mode distinct from that used by the CSF-1/CSF-1R complex (Garceau et al., 2010).