Disease relevance of Csf1r

• RESULTS AND CONCLUSIONS: Frequent spontaneous fractures and decreased strength parameters (ultimate load, yield load, and stiffness) in a three-point bending assay showed the biomechanical weakness of long bones in Csf1r(-/-) mice [1].
• Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects [2].
• This apparent role for CSF-1/CSF-1R in normal mammary gland development is very intriguing because this receptor/ligand pair has also been found to be important in the biology of breast cancer, where they regulate tumor cell invasion by a urokinase-dependent mechanism [3].
• A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model [4].
• In this study, we investigated whether an inhibitor of M-CSF receptor (c-Fms) suppresses osteoclast-dependent osteolysis in bone metastatic lesions [4].

Psychiatry related information on Csf1r

• Microglia surrounding A beta plaques in Alzheimer's disease and in the APPV717F transgenic mouse model of Alzheimer's disease have enhanced immunoreactivity for the macrophage colony-stimulating factor receptor (M-CSFR), encoded by the proto-oncogene c-fms [5].

High impact information on Csf1r

• Factor switching experiments have shown that both multi-CSF and GM-CSF act dominantly and in a factor concentration dependent manner to suppress c-fms expression [6].
• Although expression of the c-fms product (CSF-1 receptor) is normally restricted to cells of the mononuclear phagocyte series, the v-fms-coded glycoprotein can contribute to proliferative abnormalities of multiple hematopoietic lineages [7].
• This putative product of the murine c-fms gene exhibited an associated tyrosine kinase activity in immune complexes, specifically bound murine CSF-1, and, in the presence of the growth factor, was phosphorylated on tyrosine in membrane preparations [8].
• Rabbit antisera to a recombinant v-fms-coded polypeptide precipitated the feline c-fms product and specifically cross-reacted with a 165 kd glycoprotein from mouse macrophages [8].
• The feline c-fms proto-oncogene product is a 170 kd glycoprotein with associated tyrosine kinase activity [8].

Chemical compound and disease context of Csf1r

• SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model [9].
• Heat-killed B. pertussis cells were the most effective inducer of NO synthesis, followed by lipopolysaccharide and agglutinogens Fim 2 and 3 [10].
• Modulation of c-fms proto-oncogene expression was also achieved using the anti-glucocorticoid, RU-486, via oral administration to SCID mice with subsequent correlation to IHC staining [11].

Biological context of Csf1r

• We observed that, concomitant with Csf1r downregulation, 32D/WT1 cells lost the ability to undergo myeloid differentiation in response to the granulocyte macrophage colony-stimulating factor (GM-CSF) [12].
• Csf1r(-/-) mice therefore represent an ideal model system in which to investigate regulation by the osteoclast of osteoblast-mediated bone formation during development [1].
• Excision of this floxed sequence results in a null allele that in the homozygous state gives a phenotype indistinguishable of the complete Csf1r null mutant mouse [13].
• The interaction of cytoplasmic signalling molecules with CSF-1R is mediated in part by sequence motifs flanking sites of receptor tyrosine phosphorylation [14].
• These results provide genetic evidence that in NIH-3T3 cells, ras p21 is involved in signal transduction mediated by CSF-1R [15].

Anatomical context of Csf1r

• Consequently, the primary defect in osteopetrotic Csf1r(-/-) mice is severe osteoclast deficiency [1].
• While individual osteoblasts in Csf1r(-/-) mice have preserved their typical ultrastructure and matrix depositing activity, the layered organization of osteoblasts on the bone-forming surface and the direction of their matrix deposition toward the bone surface have been lost, resulting in their abnormal entrapment by matrix [1].
• Deletion of the entire kinase insert domain completely abrogates signal transduction by the CSF-1 receptor expressed in Rat-2 fibroblasts [16].
• These results strongly suggest that the interaction of signals by means of VEGFR-1 and the CSF-1 receptor plays a predominant role not only in osteoclastogenesis but also in the maintenance of bone marrow functions [17].
• The high level of CSF-1R mRNA expression by trophoblast giant cells was independent of their location around the conceptus [18].

Associations of Csf1r with chemical compounds

• To study the possible function of CSF-1 receptor autophosphorylation, two autophosphorylation sites, Tyr-706, located in the kinase insert, and Tyr-807, a residue conserved in all protein-tyrosine kinases, were changed independently to either phenylalanine or glycine [19].
• A plasmid encoding the chimeric receptor was cotransfected along with a plasmid conferring neomycin resistance into FDC-P1 cells that do not normally express c-fms or flt3 and require granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 for growth [20].
• Reverse transcriptase polymerase chain reaction (RT-PCR) showed a TMT-induced elevation in INFalpha and INFbeta mRNA levels and no elevation of INFgamma. mRNA levels of the CSF-1 receptor, c-fms, were unaltered [21].
• c-Fms and the alphavbeta3 integrin collaborate during osteoclast differentiation [22].
• Substitution of phenylalanine for tyrosine-809 in the human colony-stimulating factor 1 receptor (CSF-1R) inhibited its ability to transduce ligand-dependent mitogenic signals in mouse NIH 3T3 cells [23].

Physical interactions of Csf1r

• Specific structural proteins associated with the separate CSF-1R multimeric complexes upon CSF-1 stimulation and the presence of the distinct pools of the CSF-1R were dependent on the integrity of the microtubular network [24].
• So far among these candidate proteins, dynein, claudin and silencer of death domains co-immunoprecipitated with the CSF-1R, suggesting association [25].
• In contrast, the CSF1R/IRA960 co-precipitates poorly with IRS-2 [26].
• Transcription factor complex formation and chromatin fine structure alterations at the murine c-fms (CSF-1 receptor) locus during maturation of myeloid precursor cells [27].

Enzymatic interactions of Csf1r

• A novel 110 kDa form of myosin XVIIIA (MysPDZ) is tyrosine-phosphorylated after colony-stimulating factor-1 receptor signalling [28].
• Bacterially expressed p85 alpha SH2 domains complexed in vitro with the tyrosine phosphorylated CSF-1R KI [29].
• Their c-fms proteins were normally phosphorylated on serine and became phosphorylated on tyrosine residues contained in five tryptic peptides when the cells were exposed to M-CSF [30].
• In mouse macrophages, MAYP is tyrosine phosphorylated after activation of the colony-stimulating factor-1 receptor (CSF-1R), which also induces actin reorganization, membrane ruffling, cell spreading, polarization, and migration [31].

Regulatory relationships of Csf1r

• Blocking protein synthesis or gene transcription with metabolic inhibitors effectively prevented GM-CSF stimulated degradation of c-fms mRNA [32].
• After adding CSF-1 to M1 myeloid cells expressing CSF-1R (CSF-1 receptor), tyrosine phosphorylation of many cellular proteins occurs, which might be linked to subsequent macrophage differentiation [28].
• Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression [33].
• Expression of the c-jun proto-oncogene was activated by CSF-1R but was insensitive to the action of the catalytic domain of GAP [15].
• These data raise the possibility that the predicted negative regulatory role of Cbl in macrophages is its enhancement of ligand-induced CSF-1 R internalization/degradation [34].

Other interactions of Csf1r

• Mutation of an autophosphorylation site at tyrosine 809 in the cytoplasmic domain of human CSF-1R does not significantly reduce its ligand-stimulated tyrosine kinase activity, binding to phosphatidylinositol 3-kinase, or induction of the immediate early response genes, c-fos and junB (ref.2) [14].
• The circulating CSF-1 concentration in Csf1r(-)/Csf1r(-) mice was elevated 20-fold, in agreement with the previously reported clearance of circulating CSF-1 by CSF-1R-mediated endocytosis and intracellular destruction [2].
• Accumulation of c-Cbl and rapid termination of colony-stimulating factor 1 receptor signaling in interferon consensus sequence binding protein-deficient bone marrow-derived macrophages [35].
• Regulation of colony-stimulating factor 1 receptor signaling by the SH2 domain-containing tyrosine phosphatase SHPTP1 [36].
• In both reeler and weaver mutant mice in the adult stage, all Purkinje cells were positive for c-fms as in the wild-type controls; however, the parasagittal bands of c-fms-positive Purkinje cells were observed even in the adult staggerer mutant [37].

Analytical, diagnostic and therapeutic context of Csf1r

• MATERIALS AND METHODS: Bones of developing Csf1r(-/-) mice and their littermate controls were subjected to X-ray analysis, histological examination by light microscopy and transmission electron microscopy, and a three-point bending assay to test their biomechanical strength [1].
• Southern blot analysis of tumor DNA from six of six of these tumors failed to reveal any rearrangements in the genes for CSF-1 or the CSF-1R [38].
• Northern blot analysis demonstrated the presence in astroglia of CSF-1 mRNA and the presence of CSF-1 receptor (c-fms) mRNA in macrophage-like cells but not in astroglia [39].
• There is evidence that the CSF-1 receptor (CSF-1R) forms distinct multimeric complexes involving autophosphorylated tyrosines in its cytoplasmic region; however, these complexes are difficult to identify by immunoprecipitation, making enrichment necessary [25].
• DESIGN: Ameloblasts and odontoblasts, isolated from wt/wt frozen sections using laser capture microdissection, were analysed for csCSF-1, sCSF-1 and CSF-1R mRNA by RT-PCR [40].

References