{"gene":"CSF1R","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1985,"finding":"The c-fms proto-oncogene product is a 170 kDa glycoprotein with associated tyrosine kinase activity that specifically binds CSF-1 (M-CSF) and is phosphorylated on tyrosine in the presence of CSF-1; the murine c-fms product and the CSF-1 receptor are related or identical molecules restricted to cells of the mononuclear phagocyte lineage.","method":"Immune complex kinase assay, radioligand binding (CSF-1 binding), tyrosine phosphorylation in membrane preparations, cross-reactive antisera to v-fms-coded polypeptide","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution (ligand binding + kinase activity in immune complexes), multiple orthogonal methods, foundational study replicated by many subsequent works","pmids":["2408759"],"is_preprint":false},{"year":1987,"finding":"CSF1R (c-fms) transduction of growth signals is sufficient to confer CSF-1-responsive growth in NIH 3T3 cells. A C-terminal tyrosine residue (Tyr969) acts as a negative regulator of receptor kinase activity; its replacement by Phe969 activates oncogenic potential in conjunction with CSF-1 or other mutations, but is not sufficient alone for transformation.","method":"NIH 3T3 cotransfection transformation assay, chimeric v-fms/c-fms constructs with point mutations (Tyr969→Phe969), anchorage-independent growth assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis combined with functional transformation assay, multiple chimeric constructs tested, clear mechanistic conclusion","pmids":["3027579"],"is_preprint":false},{"year":1988,"finding":"CSF1R (c-fms) encodes the receptor for CSF-1 with an intrinsic tyrosine-specific protein kinase activity; ligand binding stimulates kinase activity, and constitutive activation (as in v-fms) or removal of the negative-regulatory C-terminal Tyr969 provides growth signals in the absence of ligand.","method":"Biochemical review synthesizing kinase assays, mutagenesis, and transformation data","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — authoritative mechanistic synthesis by the primary lab, consistent with multiple prior experimental papers; this is a review but consolidates original experimental evidence","pmids":["2852667"],"is_preprint":false},{"year":1989,"finding":"c-fms mRNA levels are regulated post-transcriptionally by a labile protein that stabilizes the transcript; transcription rate is unchanged during monocytic differentiation or TPA-induced down-regulation, but the half-life of c-fms mRNA changes from >6 h to ~30 min when protein synthesis is inhibited.","method":"Nuclear run-on transcription assay, cycloheximide chase (mRNA half-life), Northern blotting in HL-60 cells and human monocytes","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — run-on assay directly dissociates transcriptional from post-transcriptional control; cycloheximide experiments quantify mRNA stability; two cell systems tested orthogonally","pmids":["2523515"],"is_preprint":false},{"year":2003,"finding":"During osteoclastogenesis, c-Fms collaborates with αvβ3 integrin via shared activation of the ERK/c-Fos signaling pathway; normalization of osteoclastogenesis and ERK activation in β3-null cells uniquely requires c-Fms tyrosine 697, identifying this residue as the critical signaling site.","method":"Retroviral transduction of chimeric c-Fms constructs with cytoplasmic domain mutations into primary osteoclast precursors; ERK phosphorylation assays; osteoclast differentiation rescue experiments in β3-/- cells","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis of specific tyrosine residue (Y697) with functional rescue readout in primary cells, multiple constructs tested","pmids":["12618529"],"is_preprint":false},{"year":2005,"finding":"Imatinib inhibits c-Fms (CSF1R) kinase activity at therapeutic concentrations, blocking CSF-1-induced phosphorylation of c-Fms and M-CSF-dependent proliferation; this is not due to reduced c-fms expression.","method":"Phosphorylation inhibition assay (c-Fms phosphorylation in cells), M-CSF-dependent proliferation assay in cytokine-dependent cell line, Western blot for c-fms expression","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical phosphorylation inhibition assay plus functional proliferation assay; single lab but two orthogonal methods","pmids":["15637141"],"is_preprint":false},{"year":2006,"finding":"M-CSF binding to c-Fms triggers downstream signaling in osteoclasts including ERK activation; pharmacological inhibition of c-Fms kinase (Ki20227, IC50 = 2 nM) suppresses osteoclast differentiation and osteolytic bone destruction in vivo.","method":"In vitro kinase assay (IC50 determination), TRAP+ osteoclast formation assay in mouse bone marrow, in vivo bone metastasis/osteolysis model in nude rats, ovariectomy model","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase inhibition combined with in vivo functional readout; single lab","pmids":["17121910"],"is_preprint":false},{"year":2007,"finding":"STAP-2 (signal-transducing adaptor protein-2) directly binds to the PH-domain interaction site on c-Fms independently of M-CSF stimulation, suppresses M-CSF-induced tyrosine phosphorylation of c-Fms and downstream Akt and ERK activation, and inhibits M-CSF-induced macrophage migration.","method":"Co-immunoprecipitation (STAP-2 PH domain interaction with c-Fms), Western blot for c-Fms phosphorylation, Akt/ERK activation assays, macrophage migration/wound-healing assay in Raw 264.7 overexpressing STAP-2","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional downstream signaling assay and migration readout; single lab","pmids":["17512498"],"is_preprint":false},{"year":2008,"finding":"M-CSF binding to c-Fms generates a signaling complex comprising phosphorylated DAP12 (ITAM adaptor) and the non-receptor tyrosine kinase Syk in osteoclasts; c-Fms tyrosine 559 (the exclusive c-Src binding site) is required for DAP12/Syk activation and cytoskeletal reorganization; the SH2 domain of Syk and ITAM tyrosines plus transmembrane domain of DAP12 mediate the signal.","method":"Co-immunoprecipitation of DAP12/Syk complex, retroviral transduction of null precursors with wild-type or mutant DAP12/Syk, site-directed mutagenesis (c-Fms Y559, DAP12 ITAM tyrosines and transmembrane domain), cytoskeletal reorganization assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution via retroviral transduction of null cells, reciprocal co-IP, active-site mutagenesis of multiple residues with defined functional readout (cytoskeleton)","pmids":["18691974"],"is_preprint":false},{"year":2010,"finding":"The SH2-domain adaptor protein Lnk binds to c-Fms, blunts M-CSF-stimulated Akt phosphorylation (while diminishing ERK phosphorylation), reduces M-CSF-dependent macrophage migration, and restrains M-CSF-driven clonogenic macrophage progenitor expansion.","method":"Co-immunoprecipitation (Lnk binding to c-Fms), Lnk-knockout mouse bone marrow clonogenic assay, Western blot for Akt/ERK phosphorylation, macrophage migration assay","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus genetic KO with multiple functional readouts; single lab","pmids":["20571037"],"is_preprint":false},{"year":2012,"finding":"In Nf1 haploinsufficient osteoclast progenitors, M-CSF binding to c-Fms results in increased c-Fms activation and downstream hyperactivation of Erk1/2 and p90RSK, mediating gain-of-function in migration, adhesion, and bone resorption; selective c-Fms inhibition (PLX3397) attenuates these phenotypes and prevents bone loss in vivo.","method":"c-Fms phosphorylation assay, Erk1/2/p90RSK activation Western blot, migration/adhesion/pit-formation assays, PLX3397 pharmacological inhibition, in vivo OVX mouse model with micro-CT","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with defined target plus downstream signaling assays and in vivo readout; single lab","pmids":["23144792"],"is_preprint":false},{"year":2015,"finding":"X-ray co-crystallography revealed that PLX3397 inhibits CSF1R kinase by trapping the receptor in its autoinhibited conformation; this structure-guided inhibitor is potent and selective for CSF1R.","method":"X-ray co-crystallography of CSF1R kinase domain with PLX3397, structure-guided medicinal chemistry","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with direct mechanistic interpretation (autoinhibited conformation), validated in clinical context","pmids":["26222558"],"is_preprint":false},{"year":2016,"finding":"Acquired resistance to CSF-1R inhibition in recurrent glioma is driven by the tumor microenvironment: macrophage-derived IGF-1 activates PI3K pathway via tumor cell IGF-1R, and this resistance is reversible upon tumor transplantation, establishing an epistatic tumor microenvironment→IGF-1/IGF-1R→PI3K pathway.","method":"Transplantation experiments (resistance reversibility), phosphoproteomic/gene expression analysis of recurrent vs. primary GBM, IGF-1R/PI3K inhibitor combination studies in vivo","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via transplantation, pharmacological combination rescue, molecular pathway identification; multiple orthogonal methods","pmids":["27199435"],"is_preprint":false},{"year":2016,"finding":"iRhom2/ADAM17 pathway regulates CSF1R shedding from the myeloid cell surface; loss of iRhom2 leads to constitutive accumulation of membrane-bound CSF1R, enhanced CSF1R signaling, and competitive repopulation advantage of monocytes, macrophages, and dendritic cells.","method":"Degradomics screen (unbiased), iRhom2-/- mouse analysis by flow cytometry, mixed bone marrow chimera competitive repopulation assay, in vitro LSK cell growth in response to CSF1","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased screen identifies CSF1R as ADAM17 substrate, genetic KO with competitive chimera readout; single lab","pmids":["27601030"],"is_preprint":false},{"year":2018,"finding":"IL-34 signals through Csf1ra (the CSF1R ortholog in zebrafish) to attract microglial precursors to the brain during embryogenesis; in il34- or csf1ra-deficient zebrafish, embryonic macrophages fail to migrate to the anterior head and colonize the CNS, while peripheral tissue colonization is unaffected.","method":"Zebrafish genetic loss-of-function (il34 and csf1ra mutants), live imaging of macrophage migration, gain-of-function (exogenous Il34 activation), comparison of CNS vs. peripheral tissue colonization","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in zebrafish with live imaging, gain- and loss-of-function orthogonal experiments, clearly defined mechanistic pathway","pmids":["30205037"],"is_preprint":false},{"year":2019,"finding":"Deletion of FIRE (fms-intronic regulatory element), a conserved super-enhancer within the Csf1r locus, selectively ablates CSF1R expression and macrophage development in specific tissues (brain microglia, skin, kidney, heart, peritoneum) without affecting monocytes or other macrophage populations; monocytes lack surface CSF1R protein despite normal monocyte numbers.","method":"CRISPR genomic deletion of FIRE enhancer in mice, flow cytometry for tissue macrophage populations, embryonic stem cell macrophage differentiation assay, reporter expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic deletion with comprehensive tissue analysis, multiple macrophage populations characterized, clear enhancer-to-expression-to-function linkage","pmids":["31324781"],"is_preprint":false},{"year":2019,"finding":"CSF1R signaling is activated by CSF1 in T-cell lymphoma cells in an autocrine/paracrine manner leading to CSF1R autophosphorylation, and downstream activation of PI3K/AKT/mTOR signaling pathway; loss-of-function (pexidartinib inhibition and genetic knockdown) reduces T-cell lymphoma growth in vitro and in vivo.","method":"CSF1R autophosphorylation assays, phosphoproteomic and genomic screening, pharmacological inhibition (pexidartinib), loss-of-function in vitro and in vivo mouse models","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — autophosphorylation assay with multiple downstream pathway analyses and in vivo validation; single lab","pmids":["31636099"],"is_preprint":false},{"year":2019,"finding":"CSF1R is expressed on F4/80hi Kupffer cells (KCs); Csf1r inhibition reduces F4/80hi KCs by ~50% without affecting CD11bhi KCs, delays liver regeneration after partial hepatectomy, increases hepatic injury, and attenuates KC cytokine responses to stimulation.","method":"Flow cytometry of KC subsets, Csf1r-GFP reporter mice, pharmacological CSF1R inhibition in partial hepatectomy model, liver-to-body weight ratio, serum ALT, proliferation assays, in vitro KC cytokine assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with defined cellular and functional readouts in vivo; reporter mouse confirms expression; single lab","pmids":["31042769"],"is_preprint":false},{"year":2020,"finding":"CSF1R in colorectal cancer cells acts as a dependence receptor: when expressed on cancer cells, CSF1R is cleaved by caspases and constrains tumor growth (tumor suppressor function); when silenced on cancer cells, its ligands are redirected to stimulate CSF1R on M2 tumor-associated macrophages, promoting tumor progression.","method":"CSF1R reconstitution/overexpression in CRC cells, caspase cleavage assay, siRNA knockdown, co-culture competition system (CRC cells vs. macrophages), in vitro and in vivo tumor growth assays","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with co-culture mechanistic readout and in vivo validation; single lab; novel mechanistic claim (dependence receptor/caspase cleavage)","pmids":["36600555"],"is_preprint":false},{"year":2022,"finding":"A kinase-dead CSF1R point mutation (E631K in mouse, modeling human ALSP-associated mutations) acts dominantly to inhibit CSF1R signaling: heterozygous Csf1rE631K/+ mice are unresponsive to CSF1 stimulation in vitro and to exogenous CSF1-Fc in vivo, and show reduced microglial numbers and dendritic arborisation, opposite to Csf1r+/- haploinsufficiency microgliosis.","method":"Knock-in mouse model (CRISPR), bone marrow cell stimulation assay, CSF1-Fc fusion protein in vivo administration, flow cytometry and morphological analysis of microglia, comparison with Csf1r+/- mice","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with multiple in vitro and in vivo functional readouts, genetic epistasis comparison with haploinsufficient mice, mechanistic conclusion clearly supported","pmids":["35333324"],"is_preprint":false},{"year":2022,"finding":"A glycine-to-alanine substitution at position 795 of human CSF1R (G795A) confers resistance to multiple CSF1R inhibitors (PLX3397, PLX5622) without discernible gain or loss of receptor function; G795A-expressing macrophages can engraft and persist in PLX3397-treated mouse brains, enabling nontoxic microglia replacement.","method":"Biochemical and cell-based functional assays (no gain/loss of function determination), xenotransplantation of CRISPR-engineered iPSC-derived microglia (G795A) into PLX3397-treated mice, gene expression profiling, inflammatory response assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — engineered mutation with biochemical validation plus in vivo reconstitution/transplantation; multiple orthogonal assays","pmids":["36584406"],"is_preprint":false},{"year":1994,"finding":"c-Fms (CSF1R) and c-Kit operate in a functional hierarchy during bone marrow macrophage progenitor (CFU-M) production: c-Kit plays the primary role in CFU-M production and maintenance (anti-c-Kit depletes CFU-M in vivo), while c-Fms, although co-expressed with c-Kit and functional in culture, has minimal role in CFU-M proliferation in the bone marrow in vivo.","method":"Antagonistic monoclonal antibody to murine c-Fms, anti-c-Kit mAb injection in vivo, flow cytometric sorting of c-Kit+c-Fms- vs. c-Kit+c-Fms+ fractions, CFU-M clonogenic assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional hierarchy established by in vivo antibody depletion and ex vivo clonogenic assay; single lab, well-controlled","pmids":["8545103"],"is_preprint":false},{"year":1994,"finding":"CSF-1 (M-CSF) binding to c-Fms (CSF1R) on hairy cell leukemia cells induces chemokinetic and chemotactic cell movement, actin polymerization/redistribution, and cell morphology changes; this motility is modulated by αvβ3 integrin function.","method":"Video microscopy, image analysis, migration assays, F-actin staining, integrin function assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay linking CSF1R ligand stimulation to motility and cytoskeletal rearrangement; multiple readouts; single lab","pmids":["8118039"],"is_preprint":false},{"year":2009,"finding":"TGF-β1 induces c-fms (CSF1R) mRNA and cell-surface protein expression in endometrial epithelial cells, and TGF-β1-induced transmesothelial invasion is inhibited by TGF-β antagonists, linking TGF-β signaling to c-fms upregulation and invasive behavior.","method":"Real-time RT-PCR for c-fms mRNA, flow cytometry for cell-surface c-fms, 3D transmesothelial invasion assay, TGF-β pathway antagonism","journal":"Molecular human reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic dissection (correlative between TGF-β signaling, c-fms expression, and invasion); no direct genetic manipulation of c-fms","pmids":["19505996"],"is_preprint":false},{"year":2022,"finding":"CSF1/CSF1R signaling in cancer-associated fibroblasts leads to MIP-2 (CXCL2) secretion, which acts via CXCR2 on macrophages to induce suppressive and angiogenic properties; CSF1R+ macrophages promote pleural fluid accumulation by enhancing vascular permeability and destabilizing tumor vessels.","method":"Mice with CSF1R-deficient macrophages (genetic model), BLZ945 pharmacological CSF1R inhibition, vascular permeability assays, in vivo MPE models, cell-cell interaction analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic macrophage-specific CSF1R deletion plus pharmacological inhibition with defined vascular and paracrine signaling readouts; single lab","pmids":["35315360"],"is_preprint":false}],"current_model":"CSF1R (c-Fms/CD115) is a class III receptor tyrosine kinase that, upon binding its ligands CSF-1 (M-CSF) or IL-34, undergoes autophosphorylation at multiple cytoplasmic tyrosine residues (notably Y559 for c-Src/DAP12-Syk coupling, Y697 for osteoclastogenic ERK/c-Fos signaling) to activate downstream PI3K/AKT, ERK1/2, and MAPK cascades controlling survival, proliferation, differentiation, and migration of mononuclear phagocytes; a C-terminal Tyr969 negatively regulates kinase activity, and adaptor proteins STAP-2 and Lnk bind c-Fms to attenuate signaling, while ADAM17/iRhom2-mediated ectodomain shedding limits cell-surface receptor levels; the receptor's expression is post-transcriptionally stabilized by a labile protein, transcriptionally controlled by a conserved super-enhancer (FIRE), and structurally trapped in an autoinhibited conformation by kinase inhibitors such as PLX3397."},"narrative":{"mechanistic_narrative":"CSF1R (c-Fms) is the 170 kDa glycoprotein class III receptor tyrosine kinase of the mononuclear phagocyte lineage that binds CSF-1 (M-CSF), undergoes ligand-induced tyrosine autophosphorylation, and transduces signals controlling the survival, proliferation, differentiation, and migration of macrophages and osteoclasts [PMID:2408759, PMID:3027579]. Ligand engagement activates downstream PI3K/AKT and ERK1/2 cascades [PMID:17512498, PMID:31636099], and discrete cytoplasmic tyrosines parse distinct outputs: Y559 is the c-Src binding site required to assemble a DAP12/Syk signaling complex driving cytoskeletal reorganization in osteoclasts, while Y697 is the residue critical for ERK/c-Fos osteoclastogenic signaling shared with αvβ3 integrin [PMID:18691974, PMID:12618529]; a C-terminal Tyr969 acts as a negative regulator whose mutation to Phe enhances oncogenic potential [PMID:3027579]. Receptor output is restrained at multiple levels: the adaptors STAP-2 and Lnk bind c-Fms and blunt M-CSF-induced AKT/ERK activation and macrophage migration [PMID:17512498, PMID:20571037], and iRhom2/ADAM17-mediated ectodomain shedding limits cell-surface receptor accumulation [PMID:27601030]. Expression is controlled post-transcriptionally by a labile protein that stabilizes c-fms mRNA [PMID:2523515] and transcriptionally by the conserved intronic super-enhancer FIRE, whose deletion selectively ablates CSF1R and macrophage development in brain, skin, kidney, heart, and peritoneum [PMID:31324781]. In development, IL-34 acting through CSF1R directs microglial precursor colonization of the CNS [PMID:30205037], and a dominant kinase-dead CSF1R mutation modeling human ALSP reduces microglial number and arborization [PMID:35333324]. CSF1R kinase is druggable by inhibitors including PLX3397, which traps the receptor in its autoinhibited conformation [PMID:26222558], and CSF1R-targeted therapy is being exploited across osteolytic, glioma, and lymphoma settings, with characterized resistance mechanisms via microenvironmental IGF-1/IGF-1R/PI3K signaling and a G795A gatekeeper substitution [PMID:27199435, PMID:31636099, PMID:36584406].","teleology":[{"year":1985,"claim":"Established the molecular identity of the CSF-1 receptor by showing the c-fms proto-oncogene product is a glycoprotein tyrosine kinase that directly binds CSF-1, resolving whether the receptor and the oncogene product were the same molecule.","evidence":"Immune complex kinase assay, radioligand binding, and cross-reactive antisera in mononuclear phagocyte membranes","pmids":["2408759"],"confidence":"High","gaps":["Specific autophosphorylation sites and downstream effectors not yet mapped","Ligand IL-34 not yet known"]},{"year":1987,"claim":"Showed CSF1R signaling is sufficient to confer growth responsiveness and identified the C-terminal Tyr969 as an intrinsic negative regulator whose loss potentiates transformation, defining a built-in autoinhibitory brake.","evidence":"NIH 3T3 cotransfection transformation assay with Tyr969→Phe chimeric mutants","pmids":["3027579"],"confidence":"High","gaps":["Mechanism by which Tyr969 suppresses kinase activity not resolved","Adaptor proteins binding Tyr969 not identified"]},{"year":1989,"claim":"Distinguished transcriptional from post-transcriptional control of CSF1R, showing receptor mRNA abundance during differentiation is governed by a labile protein that stabilizes the transcript rather than by transcription rate.","evidence":"Nuclear run-on, cycloheximide chase, and Northern blotting in HL-60 cells and monocytes","pmids":["2523515"],"confidence":"High","gaps":["Identity of the stabilizing labile protein unknown","cis-acting mRNA element not mapped"]},{"year":2003,"claim":"Assigned a specific cytoplasmic tyrosine (Y697) to ERK/c-Fos osteoclastogenic signaling and its functional collaboration with αvβ3 integrin, beginning the parsing of CSF1R outputs by residue.","evidence":"Retroviral transduction of cytoplasmic-domain mutants into primary osteoclast precursors with ERK and differentiation rescue in β3-null cells","pmids":["12618529"],"confidence":"High","gaps":["Direct effectors recruited to Y697 not defined","Generality beyond osteoclasts untested"]},{"year":2008,"claim":"Defined the Y559–c-Src–DAP12/Syk axis required for CSF1R-driven cytoskeletal reorganization, establishing how the receptor couples to an ITAM adaptor module in osteoclasts.","evidence":"Reconstitution of null precursors with mutant DAP12/Syk, reciprocal co-IP, and site-directed mutagenesis of Y559 and ITAM residues","pmids":["18691974"],"confidence":"High","gaps":["Stoichiometry of the c-Fms/DAP12/Syk complex not resolved","Whether the same module operates in non-osteoclast macrophages unclear"]},{"year":2010,"claim":"Identified negative regulators STAP-2 and Lnk that directly bind c-Fms and attenuate M-CSF-induced AKT/ERK signaling and macrophage migration, revealing adaptor-mediated dampening of the receptor.","evidence":"Co-IP, knockout/overexpression with AKT/ERK phosphorylation and migration/clonogenic readouts (idx 7, 9)","pmids":["17512498","20571037"],"confidence":"Medium","gaps":["Binding sites on c-Fms not fully mapped for both adaptors","Single-lab studies without reciprocal cross-validation"]},{"year":2016,"claim":"Established that ectodomain shedding by the iRhom2/ADAM17 pathway limits surface CSF1R, adding a proteolytic layer of receptor regulation that controls myeloid repopulation capacity.","evidence":"Degradomics screen plus iRhom2-/- mice and competitive bone marrow chimera assays","pmids":["27601030"],"confidence":"Medium","gaps":["Cleavage site and shed fragment fate not characterized","Single-lab finding"]},{"year":2019,"claim":"Demonstrated transcriptional control of CSF1R by the conserved FIRE super-enhancer, showing tissue-selective dependence of macrophage development on this regulatory element.","evidence":"CRISPR deletion of FIRE in mice with comprehensive tissue macrophage flow cytometry and reporter analysis","pmids":["31324781"],"confidence":"High","gaps":["Transcription factors acting at FIRE not identified","Why monocytes lack surface CSF1R despite normal numbers unexplained"]},{"year":2018,"claim":"Showed IL-34 acting through CSF1R guides microglial precursor migration into the CNS during development, separating brain colonization from peripheral macrophage seeding.","evidence":"Zebrafish il34 and csf1ra loss- and gain-of-function with live imaging of macrophage migration","pmids":["30205037"],"confidence":"High","gaps":["Downstream migratory effectors not defined","Relative contribution of CSF-1 vs IL-34 in mammalian CNS not addressed here"]},{"year":2022,"claim":"Linked CSF1R kinase activity to neurodevelopmental disease by showing a dominant-negative kinase-dead mutation reduces microglial numbers, contrasting with the microgliosis of haploinsufficiency.","evidence":"CRISPR knock-in Csf1rE631K mice with CSF1 stimulation assays, CSF1-Fc in vivo, and microglial morphology versus Csf1r+/- mice","pmids":["35333324"],"confidence":"High","gaps":["Molecular basis of the dominant-negative effect on wild-type receptor not detailed","Human ALSP genotype-phenotype correlation not directly tested"]},{"year":2016,"claim":"Resolved how CSF1R kinase inhibitors work structurally and how tumors evade them, mapping a druggable autoinhibited conformation and a microenvironmental IGF-1/IGF-1R/PI3K resistance route.","evidence":"X-ray co-crystallography of CSF1R with PLX3397 (idx 11) and transplantation/phosphoproteomic resistance analysis in glioma (idx 12)","pmids":["26222558","27199435"],"confidence":"High","gaps":["Generalizability of IGF-1 resistance across tumor types not established","Structural basis of resistance mutations not in these studies"]},{"year":2022,"claim":"Engineered a CSF1R gatekeeper variant (G795A) that resists inhibitors without altering receptor function, enabling inhibitor-protected microglia replacement and providing a tool to dissect on-target inhibitor effects.","evidence":"CRISPR-engineered iPSC-derived microglia (G795A) xenotransplanted into PLX3397-treated mice with biochemical and inflammatory profiling","pmids":["36584406"],"confidence":"High","gaps":["Structural mechanism of G795A inhibitor resistance not solved here","Long-term safety of replacement microglia unassessed"]},{"year":2020,"claim":"Proposed a context-dependent dependence-receptor role for CSF1R on cancer cells, where caspase cleavage restrains tumor growth but ligand redirection to TAMs promotes progression when receptor is silenced.","evidence":"Reconstitution/knockdown in CRC cells, caspase cleavage assay, and macrophage co-culture with in vivo tumor growth","pmids":["36600555"],"confidence":"Medium","gaps":["Caspase cleavage site and pro-death signaling not mapped","Single-lab, novel mechanism awaiting independent confirmation"]},{"year":null,"claim":"How CSF1R signaling outputs are quantitatively integrated across the diverse macrophage lineages and disease contexts—and the molecular identity of post-transcriptional and FIRE-acting regulators—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Stabilizing labile mRNA-binding protein unidentified","Transcription factors at FIRE undefined","Unified model relating residue-specific signaling to cell-type-specific outcomes lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,8,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,14]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,13,15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,15,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,19,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,16,18]}],"complexes":[],"partners":["CSF1","IL34","DAP12","SYK","SRC","STAP2","LNK","ADAM17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07333","full_name":"Macrophage colony-stimulating factor 1 receptor","aliases":["CSF-1 receptor","CSF-1-R","CSF-1R","M-CSF-R","Proto-oncogene c-Fms"],"length_aa":972,"mass_kda":108.0,"function":"Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of pro-inflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding, including the ERK1/2 and the JNK pathway (PubMed:20504948, PubMed:30982609). Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor. 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Supplement","url":"https://pubmed.ncbi.nlm.nih.gov/2978516","citation_count":24,"is_preprint":false},{"pmid":"22067001","id":"PMC_22067001","title":"Anti-c-Fms antibody inhibits lipopolysaccharide-induced osteoclastogenesis in vivo.","date":"2011","source":"FEMS immunology and medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22067001","citation_count":24,"is_preprint":false},{"pmid":"8118039","id":"PMC_8118039","title":"The function of c-fms in hairy-cell leukemia: macrophage colony-stimulating factor stimulates hairy-cell movement.","date":"1994","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8118039","citation_count":24,"is_preprint":false},{"pmid":"32535390","id":"PMC_32535390","title":"Inhibition of CSF1R and AKT by (±)-kusunokinin hinders breast cancer cell proliferation.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32535390","citation_count":23,"is_preprint":false},{"pmid":"38450286","id":"PMC_38450286","title":"Deplete and repeat: microglial CSF1R inhibition and traumatic brain injury.","date":"2024","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38450286","citation_count":22,"is_preprint":false},{"pmid":"38465843","id":"PMC_38465843","title":"The Phenotypic and Genotypic Spectrum of CSF1R-Related Disorder in China.","date":"2024","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/38465843","citation_count":21,"is_preprint":false},{"pmid":"39040919","id":"PMC_39040919","title":"CSF1R-Related Disorder: Prevalence of CSF1R Variants and Their Clinical Significance in the UK Population.","date":"2024","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39040919","citation_count":21,"is_preprint":false},{"pmid":"32319217","id":"PMC_32319217","title":"SWATH-Proteomics of Ibrutinib's Action in Myeloid Leukemia Initiating Mutated G-CSFR Signaling.","date":"2020","source":"Proteomics. Clinical applications","url":"https://pubmed.ncbi.nlm.nih.gov/32319217","citation_count":20,"is_preprint":false},{"pmid":"23351989","id":"PMC_23351989","title":"Defective G-CSFR signaling pathways in congenital neutropenia.","date":"2012","source":"Hematology/oncology clinics of North America","url":"https://pubmed.ncbi.nlm.nih.gov/23351989","citation_count":19,"is_preprint":false},{"pmid":"31042769","id":"PMC_31042769","title":"Csf1r or Mer inhibition delays liver regeneration via suppression of Kupffer cells.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31042769","citation_count":19,"is_preprint":false},{"pmid":"2444833","id":"PMC_2444833","title":"Detection of c-fms and CSF-1 RNA by in situ hybridization.","date":"1987","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/2444833","citation_count":19,"is_preprint":false},{"pmid":"33609280","id":"PMC_33609280","title":"G-CSFR antagonism reduces mucosal injury and airways fibrosis in a virus-dependent model of severe asthma.","date":"2021","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33609280","citation_count":19,"is_preprint":false},{"pmid":"17512498","id":"PMC_17512498","title":"STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17512498","citation_count":19,"is_preprint":false},{"pmid":"17549395","id":"PMC_17549395","title":"Novel effect of estrogen on RANK and c-fms expression in RAW 264.7 cells.","date":"2007","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17549395","citation_count":18,"is_preprint":false},{"pmid":"35315360","id":"PMC_35315360","title":"CSF1/CSF1R signaling mediates malignant pleural effusion formation.","date":"2022","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/35315360","citation_count":17,"is_preprint":false},{"pmid":"23643873","id":"PMC_23643873","title":"Cloning and expression analysis of grouper (Epinephelus coioides) M-CSFR gene post Cryptocaryon irritans infection and distribution of M-CSFR(+) cells.","date":"2013","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23643873","citation_count":17,"is_preprint":false},{"pmid":"23144792","id":"PMC_23144792","title":"c-Fms signaling mediates neurofibromatosis Type-1 osteoclast gain-in-functions.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23144792","citation_count":17,"is_preprint":false},{"pmid":"23651419","id":"PMC_23651419","title":"An anti-c-Fms antibody inhibits osteoclastogenesis in a mouse periodontitis model.","date":"2013","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23651419","citation_count":17,"is_preprint":false},{"pmid":"40513575","id":"PMC_40513575","title":"CSF1R+ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma.","date":"2025","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/40513575","citation_count":16,"is_preprint":false},{"pmid":"34979548","id":"PMC_34979548","title":"M-CSFR/CSF1R signaling regulates myeloid fates in zebrafish via distinct action of its receptors and ligands.","date":"2022","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/34979548","citation_count":16,"is_preprint":false},{"pmid":"27601030","id":"PMC_27601030","title":"iRhom2 regulates CSF1R cell surface expression and non-steady state myelopoiesis in mice.","date":"2016","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27601030","citation_count":16,"is_preprint":false},{"pmid":"34566948","id":"PMC_34566948","title":"The CSF1R-Microglia Axis Has Protective Host-Specific Roles During Neurotropic Picornavirus Infection.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34566948","citation_count":16,"is_preprint":false},{"pmid":"12529666","id":"PMC_12529666","title":"C-fms expression correlates with monocytic differentiation in PML-RAR alpha+ acute promyelocytic leukemia.","date":"2003","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/12529666","citation_count":15,"is_preprint":false},{"pmid":"27185163","id":"PMC_27185163","title":"Resident corneal c-fms(+) macrophages and dendritic cells mediate early cellular infiltration in adenovirus keratitis.","date":"2016","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/27185163","citation_count":15,"is_preprint":false},{"pmid":"28377059","id":"PMC_28377059","title":"Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.","date":"2017","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/28377059","citation_count":14,"is_preprint":false},{"pmid":"37560003","id":"PMC_37560003","title":"Challenges and prospects of CSF1R targeting for advanced malignancies.","date":"2023","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37560003","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50181,"output_tokens":6643,"usd":0.125094,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15627,"output_tokens":4554,"usd":0.095992,"stage2_stop_reason":"end_turn"},"total_usd":0.221086,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1985,\n      \"finding\": \"The c-fms proto-oncogene product is a 170 kDa glycoprotein with associated tyrosine kinase activity that specifically binds CSF-1 (M-CSF) and is phosphorylated on tyrosine in the presence of CSF-1; the murine c-fms product and the CSF-1 receptor are related or identical molecules restricted to cells of the mononuclear phagocyte lineage.\",\n      \"method\": \"Immune complex kinase assay, radioligand binding (CSF-1 binding), tyrosine phosphorylation in membrane preparations, cross-reactive antisera to v-fms-coded polypeptide\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution (ligand binding + kinase activity in immune complexes), multiple orthogonal methods, foundational study replicated by many subsequent works\",\n      \"pmids\": [\"2408759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"CSF1R (c-fms) transduction of growth signals is sufficient to confer CSF-1-responsive growth in NIH 3T3 cells. A C-terminal tyrosine residue (Tyr969) acts as a negative regulator of receptor kinase activity; its replacement by Phe969 activates oncogenic potential in conjunction with CSF-1 or other mutations, but is not sufficient alone for transformation.\",\n      \"method\": \"NIH 3T3 cotransfection transformation assay, chimeric v-fms/c-fms constructs with point mutations (Tyr969→Phe969), anchorage-independent growth assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis combined with functional transformation assay, multiple chimeric constructs tested, clear mechanistic conclusion\",\n      \"pmids\": [\"3027579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CSF1R (c-fms) encodes the receptor for CSF-1 with an intrinsic tyrosine-specific protein kinase activity; ligand binding stimulates kinase activity, and constitutive activation (as in v-fms) or removal of the negative-regulatory C-terminal Tyr969 provides growth signals in the absence of ligand.\",\n      \"method\": \"Biochemical review synthesizing kinase assays, mutagenesis, and transformation data\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — authoritative mechanistic synthesis by the primary lab, consistent with multiple prior experimental papers; this is a review but consolidates original experimental evidence\",\n      \"pmids\": [\"2852667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"c-fms mRNA levels are regulated post-transcriptionally by a labile protein that stabilizes the transcript; transcription rate is unchanged during monocytic differentiation or TPA-induced down-regulation, but the half-life of c-fms mRNA changes from >6 h to ~30 min when protein synthesis is inhibited.\",\n      \"method\": \"Nuclear run-on transcription assay, cycloheximide chase (mRNA half-life), Northern blotting in HL-60 cells and human monocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — run-on assay directly dissociates transcriptional from post-transcriptional control; cycloheximide experiments quantify mRNA stability; two cell systems tested orthogonally\",\n      \"pmids\": [\"2523515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"During osteoclastogenesis, c-Fms collaborates with αvβ3 integrin via shared activation of the ERK/c-Fos signaling pathway; normalization of osteoclastogenesis and ERK activation in β3-null cells uniquely requires c-Fms tyrosine 697, identifying this residue as the critical signaling site.\",\n      \"method\": \"Retroviral transduction of chimeric c-Fms constructs with cytoplasmic domain mutations into primary osteoclast precursors; ERK phosphorylation assays; osteoclast differentiation rescue experiments in β3-/- cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis of specific tyrosine residue (Y697) with functional rescue readout in primary cells, multiple constructs tested\",\n      \"pmids\": [\"12618529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Imatinib inhibits c-Fms (CSF1R) kinase activity at therapeutic concentrations, blocking CSF-1-induced phosphorylation of c-Fms and M-CSF-dependent proliferation; this is not due to reduced c-fms expression.\",\n      \"method\": \"Phosphorylation inhibition assay (c-Fms phosphorylation in cells), M-CSF-dependent proliferation assay in cytokine-dependent cell line, Western blot for c-fms expression\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical phosphorylation inhibition assay plus functional proliferation assay; single lab but two orthogonal methods\",\n      \"pmids\": [\"15637141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"M-CSF binding to c-Fms triggers downstream signaling in osteoclasts including ERK activation; pharmacological inhibition of c-Fms kinase (Ki20227, IC50 = 2 nM) suppresses osteoclast differentiation and osteolytic bone destruction in vivo.\",\n      \"method\": \"In vitro kinase assay (IC50 determination), TRAP+ osteoclast formation assay in mouse bone marrow, in vivo bone metastasis/osteolysis model in nude rats, ovariectomy model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase inhibition combined with in vivo functional readout; single lab\",\n      \"pmids\": [\"17121910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STAP-2 (signal-transducing adaptor protein-2) directly binds to the PH-domain interaction site on c-Fms independently of M-CSF stimulation, suppresses M-CSF-induced tyrosine phosphorylation of c-Fms and downstream Akt and ERK activation, and inhibits M-CSF-induced macrophage migration.\",\n      \"method\": \"Co-immunoprecipitation (STAP-2 PH domain interaction with c-Fms), Western blot for c-Fms phosphorylation, Akt/ERK activation assays, macrophage migration/wound-healing assay in Raw 264.7 overexpressing STAP-2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional downstream signaling assay and migration readout; single lab\",\n      \"pmids\": [\"17512498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"M-CSF binding to c-Fms generates a signaling complex comprising phosphorylated DAP12 (ITAM adaptor) and the non-receptor tyrosine kinase Syk in osteoclasts; c-Fms tyrosine 559 (the exclusive c-Src binding site) is required for DAP12/Syk activation and cytoskeletal reorganization; the SH2 domain of Syk and ITAM tyrosines plus transmembrane domain of DAP12 mediate the signal.\",\n      \"method\": \"Co-immunoprecipitation of DAP12/Syk complex, retroviral transduction of null precursors with wild-type or mutant DAP12/Syk, site-directed mutagenesis (c-Fms Y559, DAP12 ITAM tyrosines and transmembrane domain), cytoskeletal reorganization assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution via retroviral transduction of null cells, reciprocal co-IP, active-site mutagenesis of multiple residues with defined functional readout (cytoskeleton)\",\n      \"pmids\": [\"18691974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The SH2-domain adaptor protein Lnk binds to c-Fms, blunts M-CSF-stimulated Akt phosphorylation (while diminishing ERK phosphorylation), reduces M-CSF-dependent macrophage migration, and restrains M-CSF-driven clonogenic macrophage progenitor expansion.\",\n      \"method\": \"Co-immunoprecipitation (Lnk binding to c-Fms), Lnk-knockout mouse bone marrow clonogenic assay, Western blot for Akt/ERK phosphorylation, macrophage migration assay\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus genetic KO with multiple functional readouts; single lab\",\n      \"pmids\": [\"20571037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Nf1 haploinsufficient osteoclast progenitors, M-CSF binding to c-Fms results in increased c-Fms activation and downstream hyperactivation of Erk1/2 and p90RSK, mediating gain-of-function in migration, adhesion, and bone resorption; selective c-Fms inhibition (PLX3397) attenuates these phenotypes and prevents bone loss in vivo.\",\n      \"method\": \"c-Fms phosphorylation assay, Erk1/2/p90RSK activation Western blot, migration/adhesion/pit-formation assays, PLX3397 pharmacological inhibition, in vivo OVX mouse model with micro-CT\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with defined target plus downstream signaling assays and in vivo readout; single lab\",\n      \"pmids\": [\"23144792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"X-ray co-crystallography revealed that PLX3397 inhibits CSF1R kinase by trapping the receptor in its autoinhibited conformation; this structure-guided inhibitor is potent and selective for CSF1R.\",\n      \"method\": \"X-ray co-crystallography of CSF1R kinase domain with PLX3397, structure-guided medicinal chemistry\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with direct mechanistic interpretation (autoinhibited conformation), validated in clinical context\",\n      \"pmids\": [\"26222558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Acquired resistance to CSF-1R inhibition in recurrent glioma is driven by the tumor microenvironment: macrophage-derived IGF-1 activates PI3K pathway via tumor cell IGF-1R, and this resistance is reversible upon tumor transplantation, establishing an epistatic tumor microenvironment→IGF-1/IGF-1R→PI3K pathway.\",\n      \"method\": \"Transplantation experiments (resistance reversibility), phosphoproteomic/gene expression analysis of recurrent vs. primary GBM, IGF-1R/PI3K inhibitor combination studies in vivo\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via transplantation, pharmacological combination rescue, molecular pathway identification; multiple orthogonal methods\",\n      \"pmids\": [\"27199435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"iRhom2/ADAM17 pathway regulates CSF1R shedding from the myeloid cell surface; loss of iRhom2 leads to constitutive accumulation of membrane-bound CSF1R, enhanced CSF1R signaling, and competitive repopulation advantage of monocytes, macrophages, and dendritic cells.\",\n      \"method\": \"Degradomics screen (unbiased), iRhom2-/- mouse analysis by flow cytometry, mixed bone marrow chimera competitive repopulation assay, in vitro LSK cell growth in response to CSF1\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased screen identifies CSF1R as ADAM17 substrate, genetic KO with competitive chimera readout; single lab\",\n      \"pmids\": [\"27601030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-34 signals through Csf1ra (the CSF1R ortholog in zebrafish) to attract microglial precursors to the brain during embryogenesis; in il34- or csf1ra-deficient zebrafish, embryonic macrophages fail to migrate to the anterior head and colonize the CNS, while peripheral tissue colonization is unaffected.\",\n      \"method\": \"Zebrafish genetic loss-of-function (il34 and csf1ra mutants), live imaging of macrophage migration, gain-of-function (exogenous Il34 activation), comparison of CNS vs. peripheral tissue colonization\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in zebrafish with live imaging, gain- and loss-of-function orthogonal experiments, clearly defined mechanistic pathway\",\n      \"pmids\": [\"30205037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deletion of FIRE (fms-intronic regulatory element), a conserved super-enhancer within the Csf1r locus, selectively ablates CSF1R expression and macrophage development in specific tissues (brain microglia, skin, kidney, heart, peritoneum) without affecting monocytes or other macrophage populations; monocytes lack surface CSF1R protein despite normal monocyte numbers.\",\n      \"method\": \"CRISPR genomic deletion of FIRE enhancer in mice, flow cytometry for tissue macrophage populations, embryonic stem cell macrophage differentiation assay, reporter expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic deletion with comprehensive tissue analysis, multiple macrophage populations characterized, clear enhancer-to-expression-to-function linkage\",\n      \"pmids\": [\"31324781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSF1R signaling is activated by CSF1 in T-cell lymphoma cells in an autocrine/paracrine manner leading to CSF1R autophosphorylation, and downstream activation of PI3K/AKT/mTOR signaling pathway; loss-of-function (pexidartinib inhibition and genetic knockdown) reduces T-cell lymphoma growth in vitro and in vivo.\",\n      \"method\": \"CSF1R autophosphorylation assays, phosphoproteomic and genomic screening, pharmacological inhibition (pexidartinib), loss-of-function in vitro and in vivo mouse models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — autophosphorylation assay with multiple downstream pathway analyses and in vivo validation; single lab\",\n      \"pmids\": [\"31636099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSF1R is expressed on F4/80hi Kupffer cells (KCs); Csf1r inhibition reduces F4/80hi KCs by ~50% without affecting CD11bhi KCs, delays liver regeneration after partial hepatectomy, increases hepatic injury, and attenuates KC cytokine responses to stimulation.\",\n      \"method\": \"Flow cytometry of KC subsets, Csf1r-GFP reporter mice, pharmacological CSF1R inhibition in partial hepatectomy model, liver-to-body weight ratio, serum ALT, proliferation assays, in vitro KC cytokine assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with defined cellular and functional readouts in vivo; reporter mouse confirms expression; single lab\",\n      \"pmids\": [\"31042769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CSF1R in colorectal cancer cells acts as a dependence receptor: when expressed on cancer cells, CSF1R is cleaved by caspases and constrains tumor growth (tumor suppressor function); when silenced on cancer cells, its ligands are redirected to stimulate CSF1R on M2 tumor-associated macrophages, promoting tumor progression.\",\n      \"method\": \"CSF1R reconstitution/overexpression in CRC cells, caspase cleavage assay, siRNA knockdown, co-culture competition system (CRC cells vs. macrophages), in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with co-culture mechanistic readout and in vivo validation; single lab; novel mechanistic claim (dependence receptor/caspase cleavage)\",\n      \"pmids\": [\"36600555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A kinase-dead CSF1R point mutation (E631K in mouse, modeling human ALSP-associated mutations) acts dominantly to inhibit CSF1R signaling: heterozygous Csf1rE631K/+ mice are unresponsive to CSF1 stimulation in vitro and to exogenous CSF1-Fc in vivo, and show reduced microglial numbers and dendritic arborisation, opposite to Csf1r+/- haploinsufficiency microgliosis.\",\n      \"method\": \"Knock-in mouse model (CRISPR), bone marrow cell stimulation assay, CSF1-Fc fusion protein in vivo administration, flow cytometry and morphological analysis of microglia, comparison with Csf1r+/- mice\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with multiple in vitro and in vivo functional readouts, genetic epistasis comparison with haploinsufficient mice, mechanistic conclusion clearly supported\",\n      \"pmids\": [\"35333324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A glycine-to-alanine substitution at position 795 of human CSF1R (G795A) confers resistance to multiple CSF1R inhibitors (PLX3397, PLX5622) without discernible gain or loss of receptor function; G795A-expressing macrophages can engraft and persist in PLX3397-treated mouse brains, enabling nontoxic microglia replacement.\",\n      \"method\": \"Biochemical and cell-based functional assays (no gain/loss of function determination), xenotransplantation of CRISPR-engineered iPSC-derived microglia (G795A) into PLX3397-treated mice, gene expression profiling, inflammatory response assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — engineered mutation with biochemical validation plus in vivo reconstitution/transplantation; multiple orthogonal assays\",\n      \"pmids\": [\"36584406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"c-Fms (CSF1R) and c-Kit operate in a functional hierarchy during bone marrow macrophage progenitor (CFU-M) production: c-Kit plays the primary role in CFU-M production and maintenance (anti-c-Kit depletes CFU-M in vivo), while c-Fms, although co-expressed with c-Kit and functional in culture, has minimal role in CFU-M proliferation in the bone marrow in vivo.\",\n      \"method\": \"Antagonistic monoclonal antibody to murine c-Fms, anti-c-Kit mAb injection in vivo, flow cytometric sorting of c-Kit+c-Fms- vs. c-Kit+c-Fms+ fractions, CFU-M clonogenic assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional hierarchy established by in vivo antibody depletion and ex vivo clonogenic assay; single lab, well-controlled\",\n      \"pmids\": [\"8545103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"CSF-1 (M-CSF) binding to c-Fms (CSF1R) on hairy cell leukemia cells induces chemokinetic and chemotactic cell movement, actin polymerization/redistribution, and cell morphology changes; this motility is modulated by αvβ3 integrin function.\",\n      \"method\": \"Video microscopy, image analysis, migration assays, F-actin staining, integrin function assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay linking CSF1R ligand stimulation to motility and cytoskeletal rearrangement; multiple readouts; single lab\",\n      \"pmids\": [\"8118039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TGF-β1 induces c-fms (CSF1R) mRNA and cell-surface protein expression in endometrial epithelial cells, and TGF-β1-induced transmesothelial invasion is inhibited by TGF-β antagonists, linking TGF-β signaling to c-fms upregulation and invasive behavior.\",\n      \"method\": \"Real-time RT-PCR for c-fms mRNA, flow cytometry for cell-surface c-fms, 3D transmesothelial invasion assay, TGF-β pathway antagonism\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic dissection (correlative between TGF-β signaling, c-fms expression, and invasion); no direct genetic manipulation of c-fms\",\n      \"pmids\": [\"19505996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CSF1/CSF1R signaling in cancer-associated fibroblasts leads to MIP-2 (CXCL2) secretion, which acts via CXCR2 on macrophages to induce suppressive and angiogenic properties; CSF1R+ macrophages promote pleural fluid accumulation by enhancing vascular permeability and destabilizing tumor vessels.\",\n      \"method\": \"Mice with CSF1R-deficient macrophages (genetic model), BLZ945 pharmacological CSF1R inhibition, vascular permeability assays, in vivo MPE models, cell-cell interaction analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic macrophage-specific CSF1R deletion plus pharmacological inhibition with defined vascular and paracrine signaling readouts; single lab\",\n      \"pmids\": [\"35315360\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSF1R (c-Fms/CD115) is a class III receptor tyrosine kinase that, upon binding its ligands CSF-1 (M-CSF) or IL-34, undergoes autophosphorylation at multiple cytoplasmic tyrosine residues (notably Y559 for c-Src/DAP12-Syk coupling, Y697 for osteoclastogenic ERK/c-Fos signaling) to activate downstream PI3K/AKT, ERK1/2, and MAPK cascades controlling survival, proliferation, differentiation, and migration of mononuclear phagocytes; a C-terminal Tyr969 negatively regulates kinase activity, and adaptor proteins STAP-2 and Lnk bind c-Fms to attenuate signaling, while ADAM17/iRhom2-mediated ectodomain shedding limits cell-surface receptor levels; the receptor's expression is post-transcriptionally stabilized by a labile protein, transcriptionally controlled by a conserved super-enhancer (FIRE), and structurally trapped in an autoinhibited conformation by kinase inhibitors such as PLX3397.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CSF1R (c-Fms) is the 170 kDa glycoprotein class III receptor tyrosine kinase of the mononuclear phagocyte lineage that binds CSF-1 (M-CSF), undergoes ligand-induced tyrosine autophosphorylation, and transduces signals controlling the survival, proliferation, differentiation, and migration of macrophages and osteoclasts [#0, #1]. Ligand engagement activates downstream PI3K/AKT and ERK1/2 cascades [#7, #16], and discrete cytoplasmic tyrosines parse distinct outputs: Y559 is the c-Src binding site required to assemble a DAP12/Syk signaling complex driving cytoskeletal reorganization in osteoclasts, while Y697 is the residue critical for ERK/c-Fos osteoclastogenic signaling shared with αvβ3 integrin [#8, #4]; a C-terminal Tyr969 acts as a negative regulator whose mutation to Phe enhances oncogenic potential [#1]. Receptor output is restrained at multiple levels: the adaptors STAP-2 and Lnk bind c-Fms and blunt M-CSF-induced AKT/ERK activation and macrophage migration [#7, #9], and iRhom2/ADAM17-mediated ectodomain shedding limits cell-surface receptor accumulation [#13]. Expression is controlled post-transcriptionally by a labile protein that stabilizes c-fms mRNA [#3] and transcriptionally by the conserved intronic super-enhancer FIRE, whose deletion selectively ablates CSF1R and macrophage development in brain, skin, kidney, heart, and peritoneum [#15]. In development, IL-34 acting through CSF1R directs microglial precursor colonization of the CNS [#14], and a dominant kinase-dead CSF1R mutation modeling human ALSP reduces microglial number and arborization [#19]. CSF1R kinase is druggable by inhibitors including PLX3397, which traps the receptor in its autoinhibited conformation [#11], and CSF1R-targeted therapy is being exploited across osteolytic, glioma, and lymphoma settings, with characterized resistance mechanisms via microenvironmental IGF-1/IGF-1R/PI3K signaling and a G795A gatekeeper substitution [#12, #16, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Established the molecular identity of the CSF-1 receptor by showing the c-fms proto-oncogene product is a glycoprotein tyrosine kinase that directly binds CSF-1, resolving whether the receptor and the oncogene product were the same molecule.\",\n      \"evidence\": \"Immune complex kinase assay, radioligand binding, and cross-reactive antisera in mononuclear phagocyte membranes\",\n      \"pmids\": [\"2408759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific autophosphorylation sites and downstream effectors not yet mapped\", \"Ligand IL-34 not yet known\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Showed CSF1R signaling is sufficient to confer growth responsiveness and identified the C-terminal Tyr969 as an intrinsic negative regulator whose loss potentiates transformation, defining a built-in autoinhibitory brake.\",\n      \"evidence\": \"NIH 3T3 cotransfection transformation assay with Tyr969→Phe chimeric mutants\",\n      \"pmids\": [\"3027579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Tyr969 suppresses kinase activity not resolved\", \"Adaptor proteins binding Tyr969 not identified\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Distinguished transcriptional from post-transcriptional control of CSF1R, showing receptor mRNA abundance during differentiation is governed by a labile protein that stabilizes the transcript rather than by transcription rate.\",\n      \"evidence\": \"Nuclear run-on, cycloheximide chase, and Northern blotting in HL-60 cells and monocytes\",\n      \"pmids\": [\"2523515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the stabilizing labile protein unknown\", \"cis-acting mRNA element not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Assigned a specific cytoplasmic tyrosine (Y697) to ERK/c-Fos osteoclastogenic signaling and its functional collaboration with αvβ3 integrin, beginning the parsing of CSF1R outputs by residue.\",\n      \"evidence\": \"Retroviral transduction of cytoplasmic-domain mutants into primary osteoclast precursors with ERK and differentiation rescue in β3-null cells\",\n      \"pmids\": [\"12618529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effectors recruited to Y697 not defined\", \"Generality beyond osteoclasts untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the Y559–c-Src–DAP12/Syk axis required for CSF1R-driven cytoskeletal reorganization, establishing how the receptor couples to an ITAM adaptor module in osteoclasts.\",\n      \"evidence\": \"Reconstitution of null precursors with mutant DAP12/Syk, reciprocal co-IP, and site-directed mutagenesis of Y559 and ITAM residues\",\n      \"pmids\": [\"18691974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the c-Fms/DAP12/Syk complex not resolved\", \"Whether the same module operates in non-osteoclast macrophages unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified negative regulators STAP-2 and Lnk that directly bind c-Fms and attenuate M-CSF-induced AKT/ERK signaling and macrophage migration, revealing adaptor-mediated dampening of the receptor.\",\n      \"evidence\": \"Co-IP, knockout/overexpression with AKT/ERK phosphorylation and migration/clonogenic readouts (idx 7, 9)\",\n      \"pmids\": [\"17512498\", \"20571037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding sites on c-Fms not fully mapped for both adaptors\", \"Single-lab studies without reciprocal cross-validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that ectodomain shedding by the iRhom2/ADAM17 pathway limits surface CSF1R, adding a proteolytic layer of receptor regulation that controls myeloid repopulation capacity.\",\n      \"evidence\": \"Degradomics screen plus iRhom2-/- mice and competitive bone marrow chimera assays\",\n      \"pmids\": [\"27601030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site and shed fragment fate not characterized\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated transcriptional control of CSF1R by the conserved FIRE super-enhancer, showing tissue-selective dependence of macrophage development on this regulatory element.\",\n      \"evidence\": \"CRISPR deletion of FIRE in mice with comprehensive tissue macrophage flow cytometry and reporter analysis\",\n      \"pmids\": [\"31324781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors acting at FIRE not identified\", \"Why monocytes lack surface CSF1R despite normal numbers unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed IL-34 acting through CSF1R guides microglial precursor migration into the CNS during development, separating brain colonization from peripheral macrophage seeding.\",\n      \"evidence\": \"Zebrafish il34 and csf1ra loss- and gain-of-function with live imaging of macrophage migration\",\n      \"pmids\": [\"30205037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream migratory effectors not defined\", \"Relative contribution of CSF-1 vs IL-34 in mammalian CNS not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked CSF1R kinase activity to neurodevelopmental disease by showing a dominant-negative kinase-dead mutation reduces microglial numbers, contrasting with the microgliosis of haploinsufficiency.\",\n      \"evidence\": \"CRISPR knock-in Csf1rE631K mice with CSF1 stimulation assays, CSF1-Fc in vivo, and microglial morphology versus Csf1r+/- mice\",\n      \"pmids\": [\"35333324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the dominant-negative effect on wild-type receptor not detailed\", \"Human ALSP genotype-phenotype correlation not directly tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how CSF1R kinase inhibitors work structurally and how tumors evade them, mapping a druggable autoinhibited conformation and a microenvironmental IGF-1/IGF-1R/PI3K resistance route.\",\n      \"evidence\": \"X-ray co-crystallography of CSF1R with PLX3397 (idx 11) and transplantation/phosphoproteomic resistance analysis in glioma (idx 12)\",\n      \"pmids\": [\"26222558\", \"27199435\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of IGF-1 resistance across tumor types not established\", \"Structural basis of resistance mutations not in these studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Engineered a CSF1R gatekeeper variant (G795A) that resists inhibitors without altering receptor function, enabling inhibitor-protected microglia replacement and providing a tool to dissect on-target inhibitor effects.\",\n      \"evidence\": \"CRISPR-engineered iPSC-derived microglia (G795A) xenotransplanted into PLX3397-treated mice with biochemical and inflammatory profiling\",\n      \"pmids\": [\"36584406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of G795A inhibitor resistance not solved here\", \"Long-term safety of replacement microglia unassessed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Proposed a context-dependent dependence-receptor role for CSF1R on cancer cells, where caspase cleavage restrains tumor growth but ligand redirection to TAMs promotes progression when receptor is silenced.\",\n      \"evidence\": \"Reconstitution/knockdown in CRC cells, caspase cleavage assay, and macrophage co-culture with in vivo tumor growth\",\n      \"pmids\": [\"36600555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Caspase cleavage site and pro-death signaling not mapped\", \"Single-lab, novel mechanism awaiting independent confirmation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CSF1R signaling outputs are quantitatively integrated across the diverse macrophage lineages and disease contexts—and the molecular identity of post-transcriptional and FIRE-acting regulators—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stabilizing labile mRNA-binding protein unidentified\", \"Transcription factors at FIRE undefined\", \"Unified model relating residue-specific signaling to cell-type-specific outcomes lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 8, 16]},\n      {\"term_id\": \"GO:0004888\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 13, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 15, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 19, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 16, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CSF1\", \"IL34\", \"DAP12\", \"SYK\", \"SRC\", \"STAP2\", \"LNK\", \"ADAM17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}