The CSF-1 receptor (CSF-1R) is activated with the homodimeric growth factors

The CSF-1 receptor (CSF-1R) is activated with the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). of CSF-1 IL-34 and the CSF-1R and the mechanism of ligand binding to and activation from the receptor. We further explain the pathways regulating macrophage survival proliferation differentiation and chemotaxis downstream from the CSF-1R. The glycoprotein colony-stimulating factor-1 (CSF-1) also known as macrophage-CSF (M-CSF) was the first of the CSFs to be purified (Stanley and Heard 1977) and was shown to stimulate the formation of colonies of macrophages (Stanley et al. 1978). This led to the identification (Guilbert and Stanley 1980) and purification (Yeung et al. 1987) of the CSF-1 receptor (CSF-1R) and the demonstration that it possessed intrinsic tyrosine kinase activity (Yeung et al. 1987). It was subsequently shown to be identical to the c-proto-oncoprotein (Sherr et al. 1985) previously studied by Sherr and colleagues (Rettenmier et al. 1985). The c-cDNA was cloned and shown to encode a typical class III receptor tyrosine kinase (RTK) (Coussens GSI-IX et al. 1986). The CSF-1R plays a central role in many diseases. Dominant inactivating mutations in the CSF-1R lead to adult-onset leukoencephalopathy with axonal spheroids RL and pigmented glia (Rademakers et al. 2011; Nicholson et al. 2013). Inappropriate expression of the CSF-1R contributes to the development of leukemias and lymphomas and autocrine and paracrine regulation of the CSF-1R enhances the progression and metastasis GSI-IX of solid tumors (reviewed in Pollard 2009; Chitu and Stanley 2014). In addition regulation through the CSF-1R contributes to chronic inflammatory diseases (reviewed in Chitu and Stanley 2006; Chitu et al. 2012). This review focuses on the GSI-IX CSF-1R regulation and signaling in cells of the myeloid lineage. THE CSF-1R AND LIGANDS The CSF-1R and Its Oncogenic Derivatives The CSF-1R belongs to the platelet-derived growth factor (PDGF) family. Similar to other family members it possesses a highly glycosylated extracellular region comprised of five immunoglobulin domains (D1-D5 498 amino acids) a transmembrane domain name (21 amino acids) and an intracellular area made up of a juxtamembrane area GSI-IX (JMD) (36 proteins) and an intracellular tyrosine GSI-IX kinase area (398 proteins) that’s interrupted with a kinase put area (73 proteins) (Fig. 1A) (Coussens et al. 1986; Rohrschneider and Rothwell 1987; Hampe et al. 1989). Body 1. Structure from the CSF-1R and regulation of gene expression. (proto-oncogene (oncogene encoded by the Susan McDonough strain of feline sarcoma computer virus (SM-FeSV) … Comparison of the sequences of cat c-and a v-retroviral oncogene derived from it revealed that a carboxy-terminal truncation together with two point mutations (L301S and A374S) in the extracellular D4 domain name subsequently shown to contain the dimerization interface (Elegheert et al. 2011; Ma et al. 2012) are crucial changes required for the full transforming activity of the oncogene (Fig. 1A) (Woolford et al. 1988). Another oncogenic derivative is the product of a t(3;5)(p21;q33) translocation RBM6-CSF-1R a constitutively activated CSF-1R fusion protein comprised of the amino-terminal 36 amino acids of RNA-binding motif 6 (RBM6) joined to the carboxy-terminal 399 amino acids of the CSF-1R which leads to an acute megakaryoblastic leukemia (Fig. 1A). CSF-1R Expression The CSF-1R is usually expressed at low levels on hematopoietic stem cells (HSCs) (Sarrazin et al. 2009; Mossadegh-Keller et al. 2013) at higher levels on monocytes and tissue macrophages (Guilbert and Stanley 1980; Byrne et al. 1981) osteoclasts myeloid dendritic cells (MacDonald et al. 2005) microglia (Nandi et al. 2012) and Paneth cells (Huynh et al. 2009) and controls the development of these cell types. It is also expressed on oocytes and preimplantation embryos decidual and trophoblastic cells (examined in Pollard and Stanley 1996) neural progenitor cells and other neuronal cells (Wang et al. 1999a; Nandi et al. 2012; Luo et al. 2013) renal proximal tubule epithelial cells and colonic epithelial cells (examined in Chitu and Stanley 2014). The broad pattern of expression of CSF-1R is usually consistent with its pleiotropic.