CSF1R

Summary: CSF1R activation increases downstream protein phosphorylation.

Reason: The original human-receptor reconstitution in mouse macrophages measures ligand-induced ERK phosphorylation as well as receptor phosphorylation. A receptor kinase can positively regulate downstream protein phosphorylation; its catalytic activity does not invalidate this process assertion (PMID:20504948).

Summary: CSF1R signaling contributes to myeloid differentiation.

Reason: The current ARBA00088984 branch matches the actual target features. Human receptor experiments and mouse differentiation studies support the biological claim, while the source remains electronic rather than a newly inferred human differentiation experiment. Raw provenance is preserved in CSF1R-source-evidence.yaml at rule_evaluation.rules[7].

Summary: Retain the ischemia response at its transferred, contextual scope.

Reason: The mouse donor record and PMID:8922060 describe receptor expression after cortical ischemia and CSF1-associated neuronal survival. The current response-to-ischemia definition includes changes in gene expression. These positive responses support retention without claiming that human CSF1R is an oxygen sensor or that the abstract establishes a direct human neuroprotection assay.

Summary: Retain the mouse-to-human ischemia-response inference.

Reason: The complete PMID:8922060 abstract reports mouse ischemic-lesion receptor expression and effects of exogenous CSF1. Expression responses fall within the verified term definition. The original full text was not recovered, so the specific ISS inference is retained at its contextual scope without overstating receptor-specific intervention or human experiments.

Summary: Retain broad protein kinase activity.

Reason: The InterPro kinase mappings agree with experimentally established CSF1R tyrosine-kinase activity. This broad electronic annotation is valid even though the integrated receptor activity is more informative.

Summary: CSF1R catalyzes protein-tyrosine phosphorylation.

Reason: The actual InterPro and RHEA source identifiers are preserved. Human wild-type receptor and kinase-domain mutant experiments in PMID:22197934 independently support the catalytic class; the intact 972-residue receptor, rather than the short splice product, carries the kinase domain.

Summary: Retain receptor tyrosine-kinase activity at the cited background scope.

Reason: PMID:23392676 directly investigates mouse microglial proliferation using CSF1R blockade and GW2580; its kinase statement is supporting biological context rather than a purified human kinase assay. Independent human receptor phosphorylation experiments support this established TAS activity.

Summary: Retain transmembrane receptor protein tyrosine-kinase activity.

Reason: The combined electronic sources, including the matching ARBA00027626 branch, agree with full-length receptor topology and ligand-induced human receptor phosphorylation. Donor and domain mappings are separately traceable; no equal activity is inferred for the 306-residue product.

Summary: Retain the phylogenetically supported CSF1 receptor activity.

Reason: The actual CSF1R target descends from PTN002814394 and the corresponding positive IBD is on its path. Human CSF1R is itself experimental grounding for this placement, not a circular donor. Human receptor reconstitution and ligand-binding evidence agree with the inherited function.

Summary: Retain the orthology-based receptor activity.

Reason: The exact mouse source records support CSF1 receptor function and human receptor reconstitution independently establishes the target activity. The Ensembl-derived source identity is retained without converting it into direct experimental evidence.

Summary: Human CSF1R mediates ligand-dependent signaling and proliferation.

Reason: PMID:20504948 expresses human CSF1R in a receptor-deficient cloned mouse macrophage line. Human CSF1 and IL34 elicit receptor and ERK phosphorylation and proliferation. The host is mouse, while the expressed receptor is human.

Summary: Human CSF1R confers CSF1-dependent proliferation.

Reason: The original PMID:7683918 Methods and Results use human c-fms in murine NFS60 cells, with human-receptor-specific blocking antibodies and vector controls. This demonstrates human receptor function without implying universal macrophage differentiation of these multipotent cells.

Summary: Retain the manually transferred receptor activity.

Reason: The literal mouse source record and its orthology provenance are preserved. Independent human receptor experiments establish the same ligand-responsive receptor activity, supporting the curator transfer without treating donor number as evidence strength.

Summary: Retain the established receptor activity described in the review.

Reason: The PMID:8981357 review abstract describes CSF1 action through c-fms. Its TAS statement is biologically established by the primary human receptor studies; this assessment does not claim that the review itself performed a receptor assay.

Summary: Resolve the CSF1 interaction to cytokine binding.

Reason: PMID:22153499 directly measures purified human CSF1–CSF1R ectodomain binding and assembly. CSF1 is the cognate cytokine; cytokine binding captures the positive partner class without creating an additional molecular mechanism.

Proposed replacements: cytokine binding

Summary: Resolve the CSF1 interaction to cytokine binding.

Reason: The authentic PMID:22483114 publisher supplement includes biolayer interferometry for CSF1 binding to receptor ectodomains. The complete main article was not recovered. This source-specific positive assay supports the cytokine-binding class.

Proposed replacements: cytokine binding

Summary: Resolve the IL34 interaction to cytokine binding.

Reason: The PMID:22483114 original supplement describes coexpression and purification of human IL34 with human CSF1R D1–D3 and ligand-binding measurements. Preserve the original Q6ZMJ4-1 partner. Engineered ectodomains are not evidence that the official short CSF1R splice product has equivalent function.

Proposed replacements: cytokine binding

Summary: Retain the curated CSF1 interaction as cytokine binding.

Reason: The PMID:22902366 abstract discusses BARF1 sequestration of human CSF1 and its effect on cognate receptor engagement. The original IPI names CSF1; its positive curator assertion and independently established cognate binding justify the class refinement. Detailed target panels remain unverified because full text was not accessed.

Proposed replacements: cytokine binding

Summary: Retain the curated IL34 interaction as cytokine binding.

Reason: The complete PMID:23478061 abstract explicitly reports human IL34–CSF1R extracellular assemblies by SAXS and electron microscopy. The ligand is a cytokine. Exact construct endpoints and individual measurements were not checked in full text, and the interaction is not assigned uniquely to one receptor isoform.

Proposed replacements: cytokine binding

Summary: Retain the human CSF1 interaction as cytokine binding.

Reason: The PMID:26235028 abstract reports human CSF1–CSF1R complex structures and assembly. Retain the positive curated IPI at the cognate cytokine class, without treating the unaccessed full Methods as read.

Proposed replacements: cytokine binding

Summary: Resolve the positive EPHB2 association to protein tyrosine kinase binding.

Reason: The exact PMID:35384245 records include CSF1R–EPHB2 coimmunoprecipitation and AP-MS complex expansion; both sequence ROGIDs match the recorded human backbones. EPHB2 is a receptor tyrosine kinase. Preserve the positive association under the campaign binding policy, with tagged, pervanadate-treated HEK293 assay and AP-MS spoke limits; no purified binary interaction or endogenous signaling role is inferred.

Proposed replacements: protein tyrosine kinase binding

Summary: Resolve the positive EPHA7 association to protein tyrosine kinase binding.

Reason: The exact PMID:35384245 CSF1R–EPHA7 coimmunoprecipitation and AP-MS spoke records have matching human sequence ROGIDs. EPHA7 supplies the verified tyrosine-kinase partner class. Tagged screen association is positive evidence, while native encounter, direct binary contact and functional cross-phosphorylation are unestablished.

Proposed replacements: protein tyrosine kinase binding

Summary: Resolve the surface-screen CSF1 interaction to cytokine binding.

Reason: The authentic PMID:35922511 supplement lists the CSF1R ectodomain in Table 1 and reciprocal CSF1–CSF1R raw measurements in Table 2. Table 3 independently identifies the established pair but imports affinity values from PMID:22483114; those values are not new screen measurements. The actual positive target pair and cytokine identity support this refinement.

Proposed replacements: cytokine binding

Summary: Retain ATP binding as part of the receptor kinase mechanism.

Reason: The actual kinase-domain mappings and reviewed human catalytic record support ATP binding. This does not assert an independently inspected ATP-bound structure or catalytic activity for the short splice product.

Summary: Retain the inherited plasma-membrane location.

Reason: The target lies below the actual positive PTN001230349 IBD. Current IBD donor membership is broader than the historical GOA WITH/FROM list; both snapshots are preserved separately. Human cell-surface receptor function and HPA data corroborate the location without excluding endocytic locations.

Summary: Retain the measured plasma-membrane localization.

Reason: The actual HPA XML marks plasma membrane and vesicles as supported, with cell-line-specific additional signals. Both complete subcellular records were inspected; image pixels were not. This is a gene-level immunofluorescence annotation, not evidence for isoform-exclusive localization.

Summary: Retain the combined electronic plasma-membrane assertion.

Reason: The intact receptor has a reviewed transmembrane segment and a demonstrated extracellular ligand-responsive signaling function. The exact combined source identifiers are retained, and the shorter product is not automatically assigned the same topology.

Summary: Retain the historical cell-surface receptor localization.

Reason: The PMID:2421165 abstract reports the human c-fms sequence and receptor architecture in comparison with v-fms. Full source assays were not accessed. The curated TAS location agrees with direct ligand-response experiments and HPA; no viral construct is silently treated as full human CSF1R.

Summary: Retain the membrane location in the IL34-binding event.

Reason: The actual Reactome R-HSA-6787820 graph contains plasma-membrane CSF1R entity197667 both as input and within the ligand-bound output, joined to reference entity58031/P07333. This is an entity-location assertion, not transfer of every event property to the receptor. The short cache excerpt identifies the event; the plasma-membrane assignment is supported by its preserved structured entity and compartment paths.

Summary: Retain the location of the CSF1R product of the transcription event.

Reason: In R-HSA-8853908, plasma-membrane CSF1R entity197667 is the output. Nuclear CSF1R gene entity8853905 is the input and a VENTX-containing complex is the regulator. The protein location is valid; this model does not make CSF1R the transcriptional catalyst or locate its receptor activity in the nucleus. The short cache excerpt identifies the event; the plasma-membrane assignment is supported by its preserved structured entity and compartment paths.

Summary: Retain the membrane location in the mixed-ligand event.

Reason: R-HSA-9009485 joins the CSF1R input and the CSF1R component of output complex9009491 to P07333, with plasma-membrane compartment. The structured target entity supports the location without requiring adoption of all mixed-ligand mechanistic details as new annotations. The short cache excerpt identifies the event; the plasma-membrane assignment is supported by its preserved structured entity and compartment paths.

Summary: Retain the membrane location in the IL34–SDC1 binding event.

Reason: The actual R-HSA-9009554 input and output-component paths resolve to membrane CSF1R197667 and P07333. Retain that entity-level location without inferring a separate receptor catalytic activity from the associated SDC1-containing assembly. The short cache excerpt identifies the event; the plasma-membrane assignment is supported by its preserved structured entity and compartment paths.

Summary: Qualify the broad stress-response inference while retaining the positive ischemia observations.

Reason: ARBA00026300 matches the target features, but matching a rule does not itself demonstrate participation in the predicted process. The complete original PMID:8922060 Methods, Results and Discussion show increased mouse cortical Csf1r expression after ischemia and improved neuronal survival following recombinant human CSF1 delivery. They do not perturb the receptor or establish the neuronal receptor-mediated mechanism; the authors explicitly propose that interpretation. Expression alone is therefore insufficient here to establish this broad human stress-response assignment. GO guidance permits some expression-based response annotations but also permits declining them when contribution is unresolved. The term does not require intrinsic stress sensing, and the ligand-associated neuroprotection and receptor upregulation remain positive observations. This is an overextended electronic process inference, not evidence that CSF1R cannot contribute to injury responses.

Summary: Retain the monocyte-associated inflammatory-response context.

Reason: PMID:19132917 is a monocyte biology review. CSF1R signaling contributes to mononuclear-phagocyte maintenance and inflammatory responses, while the cited TAS scope is background synthesis rather than a new direct human inflammatory assay.

Summary: Refine the broad signaling statement to the CSF1 pathway.

Reason: The PMID:8981357 review concerns CSF1 action through c-fms. The existing broad signal-transduction assertion can be represented more informatively by the source-supported macrophage colony-stimulating factor signaling pathway, without using this source to assert an IL34 experiment.

Proposed replacements: macrophage colony-stimulating factor signaling pathway

Summary: Retain the conserved receptor tyrosine-kinase signaling pathway.

Reason: The exact positive IBD is on the target path and agrees with human receptor phosphorylation and downstream signaling. The current IBD has additional donors relative to the original GOA row; the historical source fields remain unchanged and the release difference does not invalidate the ancestral placement. Raw provenance is preserved in CSF1R-source-evidence.yaml at phylogeny.joins[2], donor_records.joins[74], donor_records.joins[75], donor_records.joins[76], donor_records.joins[77], donor_records.joins[78], donor_records.joins[79], donor_records.joins[80], donor_records.joins[81], donor_records.joins[82], donor_records.joins[83], donor_records.joins[84], donor_records.joins[85], donor_records.joins[86], donor_records.joins[87], donor_records.joins[88], donor_records.joins[89], donor_records.joins[90], donor_records.joins[91], donor_records.joins[92], donor_records.joins[93], donor_records.joins[94], donor_records.joins[95], donor_records.joins[96], donor_records.joins[97], donor_records.joins[98], donor_records.joins[99], donor_records.joins[100], donor_records.joins[101], donor_records.joins[102], donor_records.joins[103], donor_records.joins[104], donor_records.joins[105], donor_records.joins[106], donor_records.joins[107], donor_records.joins[108], donor_records.joins[109], donor_records.joins[110], donor_records.joins[111], donor_records.joins[112], donor_records.joins[113], donor_records.joins[114], donor_records.joins[115], donor_records.joins[116], donor_records.joins[117], donor_records.joins[118], donor_records.joins[119], donor_records.joins[120], donor_records.joins[121], donor_records.joins[122], donor_records.joins[123], donor_records.joins[124], donor_records.joins[125], donor_records.joins[126], donor_records.joins[127], donor_records.joins[128], donor_records.joins[129], donor_records.joins[130], donor_records.joins[131], donor_records.joins[132], donor_records.joins[133], donor_records.joins[134], donor_records.joins[135], donor_records.joins[136].

Summary: Retain electronic receptor tyrosine-kinase signaling support.

Reason: The exact combined mappings agree with the full-length receptor architecture and actual ligand-induced phosphorylation. These sources support the conserved signaling mechanism without establishing every downstream branch or equivalence of both products. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[137], rule_evaluation.official_xrefs.InterPro.

Summary: Retain the curator-transferred receptor signaling pathway.

Reason: The exact ortholog source records and human ligand-response evidence agree on receptor tyrosine-kinase signaling. The ISS identity is preserved; it is not reclassified as a human experiment. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[138].

Summary: The precise axon-guidance interpretation remains unresolved.

Reason: The full available PMID:22542597 main Methods, Results and Discussion were read, including the callosal-crossing and GFAP-positive midline-cell experiments. Global mouse Csf1r loss causes failed crossing, whereas the Nestin conditional model differs; the authors propose a non-cell-autonomous contribution through survival and development of midline-support cells. The current axon-guidance term specifies growth-cone chemotactic migration. These positive developmental results do not resolve the receptor-dependent guidance step, and do not establish that secondary microglial loss is the sole explanation. UNDECIDED records this mechanistic uncertainty despite full main-text access; it does not imply that the paper was inaccessible or that axon guidance is disproved.

Summary: Refine the electronic proliferation claim to positive regulation.

Reason: The target matches ARBA00028712 and ARBA00035743. Human receptor gain-of-function reconstitution establishes CSF1-dependent proliferation, so positive regulation is a more informative target-level synthesis. This refinement does not rewrite the original rule output. Raw provenance is preserved in CSF1R-source-evidence.yaml at rule_evaluation.rules[6].

Proposed replacements: positive regulation of cell population proliferation

Summary: Refine proliferation to its positive regulatory direction.

Reason: PMID:7683918 human-receptor expression produces antibody-sensitive CSF1-dependent growth in murine multipotent NFS60 cells. Positive regulation is supported, while a macrophage-specific proliferation replacement would overstate the identity of this host cell line.

Proposed replacements: positive regulation of cell population proliferation

Summary: Refine the review-level proliferation statement to positive regulation.

Reason: The PMID:8981357 CSF1 review and independently demonstrated receptor-dependent growth establish the positive direction. Preserve the original TAS source rather than treating the review as a direct proliferation experiment.

Proposed replacements: positive regulation of cell population proliferation

Summary: Retain the inherited positive regulation of proliferation.

Reason: The actual positive IBD lies on the CSF1R target path and agrees with human receptor-dependent growth. The current IBD adds one zebrafish donor relative to the original list; that release difference is documented without changing the historical WITH/FROM. Raw provenance is preserved in CSF1R-source-evidence.yaml at phylogeny.joins[3], donor_records.joins[140], donor_records.joins[141], donor_records.joins[142], donor_records.joins[143], donor_records.joins[144], donor_records.joins[145], donor_records.joins[146], donor_records.joins[147], donor_records.joins[148], donor_records.joins[149], donor_records.joins[150], donor_records.joins[151], donor_records.joins[152], donor_records.joins[153], donor_records.joins[154], donor_records.joins[155].

Summary: Retain the electronic positive-proliferation assertion.

Reason: The combined source mappings agree with actual human-receptor-dependent proliferation. Cell identity and experimental context remain source-specific; this annotation does not claim that CSF1R increases proliferation in every lineage. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[156], rule_evaluation.rules[2].

Summary: Refine the human-receptor experiment to macrophage proliferation.

Reason: PMID:20504948 reconstitutes human CSF1R in a cloned receptor-deficient mouse macrophage line and measures ligand-induced proliferation. The macrophage-specific positive-regulation term fits this experiment; the host cells are not human macrophages.

Proposed replacements: positive regulation of macrophage proliferation

Summary: Retain context-dependent inhibition of neural progenitor expansion.

Reason: The actual PMID:22542597 mouse study includes microglia-free dorsal forebrain clones in which CSF1 or IL34 suppresses progenitor self-renewal and enhances differentiation, plus conditional-loss evidence. This context-specific effect is compatible with pro-proliferative myeloid signaling and is not generalized to human neurons.

Summary: Retain the transferred cell-shape regulation at contextual scope.

Reason: Literal donor records support the orthology assertion, and the human MCF10A source independently shows receptor-dependent epithelial shape and architecture changes. Retain this downstream signaling output without inferring a direct cytoskeletal structural activity. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[158].

Summary: Retain receptor-dependent epithelial cell-shape changes.

Reason: The full PMID:15117969 MCF10A experiments use autocrine receptor/ligand expression and constitutively active receptor constructs, with Y561/Src controls. They show genuine shape and architecture changes in this engineered human context, not a universal physiological epithelial role.

Summary: Retain broad morphogenesis as a contextual signaling role.

Reason: ARBA00026583 has a verified target-matching branch. Actual epithelial architecture experiments and developmental receptor-loss phenotypes support a broad morphogenetic role. Its generality and non-core status do not establish an erroneous electronic assertion. Raw provenance is preserved in CSF1R-source-evidence.yaml at rule_evaluation.rules[1].

Summary: Retain the orthology-based cell-surface location.

Reason: The exact mouse source records agree with the demonstrated human cell-surface receptor. This location is compatible with subsequent endocytosis and is not asserted to describe the short splice product independently.

Summary: Retain the curated cell-surface transfer.

Reason: The original ortholog identifiers and literal source records are preserved. Human ligand-responsive receptor function supports cell-surface localization; no exclusivity across products or cellular trafficking states is inferred.

Summary: Retain the source-qualified cell-surface inference.

Reason: The PMID:8922060 abstract concerns mouse ischemic-lesion receptor expression, while the existing ISS supplies the curator transfer. Full source localization assays were not accessed. Independent human receptor and HPA evidence support the broad target location without inventing a human neuronal surface assay.

Summary: Retain the curated macrophage-chemotaxis role with its source limit.

Reason: The PMID:26754294 abstract reports an IL34-associated macrophage recruitment loop in hepatocellular carcinoma. It does not reveal the complete CSF1R genetic-interaction panel. Preserve the positive experimental curator assertion at contextual scope, with direct receptor-specific assay details unverified; the ordinary qualifier is not a separate scientific argument.

Summary: Retain the valid broad membrane annotation.

Reason: The intact human receptor is an integral membrane protein, and the orthology-derived membrane assertion is true at that resolution. Finer plasma-membrane annotations already exist; broad electronic membrane support need not be rejected or made isoform-exclusive.

Summary: Retain the phylogenetically supported migration role.

Reason: The positive IBD lies on the actual target path and the receptor has experimental migration-related signaling outcomes. Receptor signaling can contribute to a process without being its motor. Retain this contextual process alongside existing more specific migration-regulation assertions. Raw provenance is preserved in CSF1R-source-evidence.yaml at phylogeny.joins[4], donor_records.joins[163], donor_records.joins[164], donor_records.joins[165], donor_records.joins[166], donor_records.joins[167], donor_records.joins[168], donor_records.joins[169], donor_records.joins[170], donor_records.joins[171], donor_records.joins[172], donor_records.joins[173], donor_records.joins[174], donor_records.joins[175], donor_records.joins[176], donor_records.joins[177].

Summary: Retain tyrosine phosphorylation by the activated receptor.

Reason: The human-receptor experiment in PMID:20504948 measures ligand-responsive receptor pY723; independent human kinase-domain mutant experiments corroborate tyrosine autophosphorylation. Mouse phosphosite lists are not transferred as a human site catalogue.

Summary: Retain broad cytokine-mediated signaling from the domain mapping.

Reason: The InterPro source is compatible with the established cytokine-responsive receptor. The broader electronic assertion remains valid while source-specific human experiments are refined to the CSF1 and IL34 pathways.

Summary: Represent both experimentally supported cytokine pathways.

Reason: The original PMID:20504948 human-receptor reconstitution tests human CSF1 and IL34 and measures downstream signaling. Current GO includes both macrophage colony-stimulating factor signaling and interleukin-34-mediated signaling, each under cytokine-mediated signaling. The historical claim that an IL34-specific term is unavailable is superseded.

Proposed replacements: macrophage colony-stimulating factor signaling pathway interleukin-34-mediated signaling pathway

Summary: Retain the conserved growth-factor binding assertion.

Reason: The actual positive IBD lies on the CSF1R path, and binding of the cognate cytokine growth factors is directly established. Their growth-factor and cytokine classes are compatible; the broad ancestral term is not an assertion of arbitrary growth-factor specificity.

Summary: Retain phosphatase binding with the substrate-trapping limitation.

Reason: PMID:16705167 demonstrates CSF1R association with a trapping Tcptp mutant and receptor hyperphosphorylation in Tcptp-deficient macrophages; the wild-type trapping comparison is negative. The binding definition does not exclude an enzyme–substrate contact. Preserve the positive ortholog-derived association without claiming that CSF1R itself is a phosphatase or that this assay establishes a stable wild-type complex. The complete PMID:11157073 abstract additionally reports SHP1 association with CSF1R in microglia from a rat/mouse CNS study; this corroborates the partner class without establishing a human-specific assay or replacing the original transfer.

Summary: Retain cytokine binding with species-specific assay attribution.

Reason: Cytokine binding is directly established by human structural and binding studies. In PMID:20504948 itself, quantitative competitive binding uses mouse receptor, whereas the human-receptor experiment demonstrates signaling and proliferation. Preserve the curated IDA and its original reference with this assay distinction.

Summary: Retain the electronic cytokine-binding assertion.

Reason: The combined source mappings agree with actual human CSF1 and IL34 binding. The electronic source identities are retained; no new ligand specificity or activity of the short splice product is inferred.

Summary: Retain the mouse structural transfer of cytokine binding.

Reason: The actual PMID:19017797 main text describes mouse MCSF and FMS ectodomain constructs, including D1–D3 and D1–D5. These are genuine binding experiments supporting the curator transfer, independently corroborated in human; the detailed separate supplement was not read.

Summary: Retain the contextual olfactory-bulb developmental role.

Reason: The actual PMID:22542597 mouse study reports olfactory-bulb atrophy and altered survival, with broader receptor-dependent neural and microglial developmental effects. This supports the transferred developmental role at tissue-system scope, not a direct human olfactory-neuron assay or a separate receptor molecular activity.

Summary: Retain the source-qualified forebrain differentiation role.

Reason: PMID:22542597 includes microglia-free mouse forebrain clones, ligand-dependent differentiation and neural-progenitor conditional receptor loss. Preserve the positive transferred context without claiming that neuronal CSF1R expression or this role is established identically in human.

Summary: Retain electronic regulation of morphogenesis.

Reason: The actual ARBA00091911 branch matches the target, and receptor-dependent epithelial architecture and cell-shape experiments support a morphogenetic signaling output. This is contextual regulation rather than an independent structural core. Raw provenance is preserved in CSF1R-source-evidence.yaml at rule_evaluation.rules[10].

Summary: Retain the broad hematopoietic process at its tested scope.

Reason: PMID:7683918 human CSF1R supports long-term growth of multipotent NFS60 cells while preserving erythroid differentiation potential. This is compatible with broad hematopoiesis, but is not an experiment establishing all hematopoietic lineages as normal receptor targets.

Summary: Retain monocyte differentiation described in the IL34 review.

Reason: The PMID:30066957 abstract summarizes IL34/CSF1R effects on monocyte and macrophage biology. Retain the established NAS process with review-level provenance, not a claimed new human differentiation experiment from that review.

Summary: Retain monocyte differentiation at review-level scope.

Reason: PMID:19132917 discusses monocyte development and CSF1R biology. The accepted role is consistent with primary receptor differentiation work, while the original TAS citation remains background synthesis.

Summary: Retain the macrophage differentiation assertion.

Reason: PMID:22153499 states mononuclear-phagocyte differentiation as biological context; its performed experiments address extracellular receptor assembly. Independent receptor biology supports the NAS process, without recasting the structural study as a human macrophage differentiation assay.

Summary: Retain the established macrophage differentiation role.

Reason: The PMID:19132917 review provides the original TAS context. Receptor-mediated signaling contributes to macrophage differentiation, while the review itself is not credited with performing the underlying experiments.

Summary: Retain the inherited osteoclast differentiation role.

Reason: The exact positive IBD is on the target path and its descendant evidence agrees with receptor-dependent osteoclast biology. The receptor supplies signaling that contributes to differentiation; it is not merely a consumed substrate or a bone structural component.

Summary: Retain the orthology-based osteoclast differentiation assertion.

Reason: The exact mouse donor records and the source-qualified receptor/differentiation literature support the transfer. Human skeletal phenotypes are corroborative context, not alone a mechanistic assay.

Summary: Retain the curated osteoclast differentiation transfer.

Reason: The preserved ortholog source assertion is consistent with receptor-mediated osteoclast differentiation and independent mouse receptor experiments. Human biallelic skeletal disease corroborates physiological relevance without substituting for experimental process evidence.

Summary: Retain the inherited positive migration regulation.

Reason: The actual positive IBD lies on the target path. Human epithelial receptor experiments and macrophage signaling contexts support positive migration regulation, which remains a contextual output of the receptor mechanism rather than an additional molecular-function core. Raw provenance is preserved in CSF1R-source-evidence.yaml at phylogeny.joins[7], donor_records.joins[197], donor_records.joins[198], donor_records.joins[199].

Summary: Retain orthology-based ruffle organization.

Reason: The literal mouse donor records support the existing assertion and are preserved separately from later source interpretations. Receptor-driven cytoskeletal remodeling is compatible with this contextual output; individual donor full-text ruffling assays were not newly read. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[200].

Summary: Retain the curated ruffle-organization transfer.

Reason: The actual ortholog records preserve the curator judgment. CSF1R-mediated cytoskeletal responses support biological plausibility; this assessment does not claim a new human ruffle assay or an independently reread full donor paper. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[201].

Summary: Retain cytokine-induced chemokine production in human blood.

Reason: The complete PMID:20829061 abstract reports human whole-blood chemokine induction by MCSF or IL34 and inhibition by GW2580. Retain the positive experimental annotation with the abstract-only access limit and mixed-cell context; receptor genetic specificity was not independently verified from full Methods.

Summary: Retain transferred actin-cytoskeleton regulation.

Reason: The literal mouse source records support the conserved signaling output. Actual human epithelial experiments corroborate receptor-dependent architecture and junction-associated cytoskeletal changes, without making CSF1R an actin motor or transferring exact donor constructs. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[202].

Summary: Retain curated regulation of actin organization.

Reason: The original ortholog transfer is preserved and compatible with receptor-driven cytoskeletal signaling. Its precise donor experimental panel was not fully reread; independently examined human epithelial evidence supports contextual retention, not universal cell-type equivalence. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[203].

Summary: Retain the electronic cellular response to CSF1.

Reason: ARBA00090245 matches the target and the combined donor mappings agree with measured ligand-responsive receptor signaling and proliferation. This broad response assertion remains valid alongside the specific CSF1 pathway.

Summary: Retain the measured cellular response to human CSF1.

Reason: The PMID:20504948 human-receptor reconstitution measures ligand-dependent signaling and proliferation in a cloned mouse macrophage host. The response is attributable to the expressed human receptor without claiming human host cells.

Summary: Retain the antibody-sensitive response mediated by human CSF1R.

Reason: The PMID:7683918 original experiments establish CSF1-dependent growth after human c-fms expression and inhibition by human-receptor-specific antibodies. This is a direct cellular response in the tested murine host.

Summary: Retain the transferred CSF1 signaling pathway.

Reason: The exact mouse source records agree with independently established human ligand-responsive receptor signaling. The source identity remains electronic; no additional source-specific human experiment is invented.

Summary: Retain the curated CSF1 pathway transfer.

Reason: The original ortholog source identifiers and actual current records support the conserved pathway, corroborated by human CSF1R reconstitution. The ISS evidence code and its scope are retained.

Summary: Retain the CSF1 pathway described in the IL34 review.

Reason: The PMID:30066957 abstract discusses the shared receptor and overlapping CSF1/IL34 biology. The existing NAS CSF1 pathway is correct; this review-level source is not presented as a new direct signaling assay.

Summary: Retain the contextual STAT-phosphorylation branch.

Reason: The actual mouse donor records and reviewed receptor signaling context support the existing transfer. Preserve the positive curator assertion while distinguishing downstream STAT phosphorylation from a newly demonstrated direct CSF1R–STAT catalytic assay in human. Raw provenance is preserved in CSF1R-source-evidence.yaml at donor_records.joins[207].

Summary: Retain ligand-dependent receptor homodimerization.

Reason: The orthology assertion agrees with actual human receptor ectodomain assembly. PMID:22153499 attributes homotypic contacts to D4, while a direct D5 contribution remains unresolved. This is ligand-associated receptor assembly, not constitutive dimerization or demonstrated oligomerization of the short splice product.

Summary: Retain the contextual survival-promoting role.

Reason: The mouse donor evidence includes increased cortical apoptosis with receptor loss, and PMID:22542597 explicitly distinguishes possible direct progenitor survival effects from secondary lineage changes. Preserve anti-apoptotic signaling at that scope without assigning a direct anti-caspase activity.

Summary: Retain the conserved signaling-receptor complex.

Reason: The actual positive IBD lies on the target path. The current IBD lacks A6QR62 present in the historical row; both source snapshots remain explicit. Human CSF1 and IL34 receptor assemblies independently support the broad complex assertion, without making the IL34 complex the CSF1-named complex.

Summary: Name the CSF1 complex directly characterized by this source.

Reason: PMID:22153499 characterizes purified human CSF1–CSF1R extracellular assembly. GO:1990682 identifies this ligand-specific complex more precisely. Its current typed closure does not contain GO:0043235, so this is semantic precision based on the source, not a claimed ontology child relationship.

Proposed replacements: CSF1-CSF1R complex

Summary: Retain the general receptor-complex term for IL34 assembly.

Reason: The PMID:22483114 original supplement supports the human IL34–CSF1R ectodomain complex. A CSF1-named complex would misidentify this ligand. Preserve the generic receptor-complex annotation and the engineered-construct/packing limits.

Summary: Retain the inherited MAPK regulatory role.

Reason: The actual positive IBD lies on the target path. Human receptor reconstitution directly measures ligand-dependent ERK phosphorylation, supporting regulation of this downstream pathway without asserting that CSF1R catalyzes every MAPK cascade step.

Summary: The viral-output phenotype is positive, but the specific host viral-process attribution is overextended.

Reason: The original PMID:20889566 mouse experiments delete Igf2r using Csf1r-promoter Cre, not Csf1r; that donor rationale is miscited for CSF1R. Separately, PMID:25060299 reports significantly reduced extracellular HIV p24 with 470 nM GW2580 in primary human fetal microglia. The all-points ligand comparison is nonsignificant; a ligand trend becomes significant only after exclusion of one control outlier, whereas the inhibitor contrasts are reported separately as significant. This is a real pharmacological phenotype, but receptor genetic confirmation, target engagement and quantitative viable-cell normalization are absent. The data do not distinguish CSF1R-mediated regulation of viral activity from a permissive host-cell state or maintenance effect. GO:0044794 permits indirect host regulation and does not require physical viral contact; the problem is insufficient causal specificity for that process, not proof that CSF1R cannot contribute or that maintenance is the sole mechanism. MARK_AS_OVER_ANNOTATED therefore preserves the positive phenotype while qualifying the process attribution. The manuscript Methods list three inhibitor doses while final publisher Methods list 470 nM only; the shared reported 470 nM result is used without claiming a dose-response. The original transfer tuple and SOURCE_BAD donor assessment remain unchanged.

Summary: Retain the broad innate-immune role at background scope.

Reason: PMID:22153499 discusses the mononuclear-phagocyte functions of the receptor as context for structural experiments. CSF1R-dependent maintenance and differentiation contribute to innate immunity; this NAS statement is not a performed pathogen-response assay in that paper.

Summary: Retain the contextual regulation of bone resorption.

Reason: The original rat transfer is preserved. The additional PMID:17121910 abstract reports effects of Ki20227 on osteoclast-related endpoints and bone resorption, with kinase selectivity limitations; it is corroboration rather than proof from a perfectly selective inhibitor. No direct CSF1R bone-dissolving activity is asserted.

Summary: Represent the experimentally observed inhibition of cadherin adhesion.

Reason: The complete PMID:15117969 human MCF10A experiments show receptor-dependent E-cadherin internalization and loss of junctional integrity, with Y561/Src controls and preserved cadherin–catenin complex composition. Negative regulation of cadherin-mediated cell adhesion describes the actual effect more precisely than junction maintenance. The engineered autocrine context is retained rather than rejected simply for being nonphysiological.

Proposed replacements: negative regulation of cell-cell adhesion mediated by cadherin

Summary: Retain ligand-induced receptor autophosphorylation.

Reason: The PMID:20504948 human-receptor experiment measures pY723 after ligand stimulation. Independent human mutant experiments support autophosphorylation, but mouse sites and the separate clinical-paper phosphosite discrepancy are not converted into a definitive human site catalogue.

Summary: Retain organ development at the demonstrated neural signaling scope.

Reason: ARBA00029247 has target-matching branches. The actual PMID:22542597 mouse study goes beyond global brain abnormalities after microglial loss: purified Nestin-GFP forebrain progenitor cultures respond to CSF1 or IL34 with altered self-renewal and neuronal differentiation, and neural-progenitor Csf1r deletion produces smaller brains and altered progenitor/apoptosis phenotypes despite normal microglial development. Receptor-mediated control of progenitor maturation contributes to organ formation and satisfies the current development definition at this context. Some global abnormalities were not reproduced by neural deletion, so microglial and other indirect contributions remain distinct. Retain the broad annotation as non-core without asserting that every tissue phenotype is direct, that all organs are specified by CSF1R, or that these are human neural experiments.

Summary: Retain the transferred PI3K–AKT signaling branch.

Reason: The exact mouse donor records support this downstream receptor-signaling assertion. Preserve the positive pathway regulation while avoiding an unverified human phosphosite-to-effector map or a claim that the receptor itself catalyzes the lipid-kinase reaction.

Summary: Retain curated PI3K–AKT pathway regulation.

Reason: The literal ortholog evidence is preserved and consistent with established receptor signaling. The precise donor full-text experiments were not newly read; this is source-qualified retention of the positive curator assertion, not a newly demonstrated human direct interaction.

Summary: Retain the background mammary-development statement with its source distinction.

Reason: PMID:15117969 introduces prior normal mammary development findings but performs engineered human acinar architecture and motility experiments. Acini are not a direct normal duct-morphogenesis assay. Preserve the TAS developmental context without presenting the performed experiments as proof of physiological duct development.

Summary: Retain activation of SRC-family tyrosine kinases.

Reason: The PMID:7681396 abstract directly reports CSF1-induced activation of Src, Fyn and Yes and their association with receptor complexes. Full source constructs and site assignments were not accessed. Preserve the positive experimental downstream activity without inventing a human docking-site map.

Summary: Retain CSF1R-dependent microglial proliferation.

Reason: The exact mouse donor assertion is supported by the actual PMID:23392676 mouse prion-model experiments using receptor blockade, ligands and GW2580. Human postmortem expression in that study is corroboration, not a human intervention assay.

Summary: Retain orthology-based positive ERK-pathway regulation.

Reason: The exact donor records agree with the directly observed human-receptor-dependent ERK phosphorylation in PMID:20504948. This is positive downstream pathway regulation without assigning every intermediate or a mouse phosphosite to human CSF1R.

Summary: Retain the curated ERK-pathway transfer.

Reason: The actual ortholog source records and independent human ligand-response experiment support this branch. Preserve ISS provenance and avoid unsupported direct CSF1R phosphorylation of ERK itself.

Summary: Retain the broad cytokine-response assertion.

Reason: The preserved donor records agree with established human responses to CSF1 and IL34. The broad response term is compatible with the two specific signaling pathways and does not require a redundant new annotation.

Summary: Retain the curated cytokine-response transfer.

Reason: The original ortholog sources and actual human receptor reconstitution support the broad cellular response. The source remains ISS, not reclassified as a new human experiment.

Summary: Retain the established macrophage-proliferation role with a citation limit.

Reason: Independent human-receptor experiments establish positive macrophage proliferation. PMID:26754294 itself is abstract-only here and describes an IL34-associated tumor/macrophage loop; its exact CSF1R genetic-interaction panel remains unverified. Preserve the curator-positive annotation with explicit deference rather than claim that the abstract proves the panel.

Summary: Retain electronic regulation of macrophage migration.

Reason: ARBA00089584 matches the actual target, and the combined donor assertions are preserved. The PMID:20489731 abstract reports ligand-dependent migration differences in mouse J774A.1 cells. Retain a contextual signaling output, not a direct motility machinery activity.

Summary: Retain the curated macrophage-migration transfer.

Reason: The literal ortholog source records support the existing judgment. Source-qualified mouse ligand/migration evidence is compatible with the target pathway; no direct human macrophage assay is inferred from the abstract alone.

Summary: Retain the inherited CSF1–CSF1R complex.

Reason: The target lies below PTN002814394 and the exact positive IBD is on its path. Direct human CSF1 assembly is descendant experimental grounding. The named complex does not imply that IL34 belongs to the same ligand-specific assembly.

Summary: Retain the directly characterized human CSF1 complex.

Reason: PMID:22153499 measures the purified human complex containing a CSF1 dimer and two receptor ectodomains. The ectodomain structure and solution experiments support the named complex, not equivalent signaling by the official short splice product.

Summary: Retain the orthology-based CSF1 complex assertion.

Reason: The exact mouse source records and direct human structural evidence agree on the named ligand–receptor complex. This transfer is preserved separately from human experimental annotations and is not generalized to IL34.

Summary: Retain the structural complex transfer with construct limits.

Reason: PMID:19017797 studies mouse ligand and receptor ectodomains. D1–D3 and D1–D5 differ in assembly and affinity; the human complex is independently characterized. Preserve the ISS assertion without claiming that every truncated construct has full-length stoichiometry.

Summary: Retain the demonstrated positive effect on epithelial motility.

Reason: The actual PMID:15117969 MCF10A experiments measure increased motility under receptor activation, including wound assays with mitomycin C to separate proliferation effects. The engineered human epithelial context is real positive evidence, without establishing the same behavior in every normal tissue.