{"gene":"SIRPA","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1996,"finding":"SHPS-1 (SIRPA) was identified as a transmembrane glycoprotein with three extracellular Ig-like domains and four cytoplasmic YXX(L/V/I) motifs that undergo tyrosine phosphorylation in response to mitogens (serum, insulin, LPA) and cell adhesion, leading to direct association with SHP-2 via its SH2 domains, functioning as a docking protein for SHP-1 and SHP-2.","method":"cDNA cloning, co-immunoprecipitation, in vitro kinase assay, purification from v-src-transformed fibroblasts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — original cloning paper with biochemical reconstitution of phosphorylation and SH2-domain binding, replicated in multiple subsequent studies","pmids":["8943344"],"is_preprint":false},{"year":1998,"finding":"In macrophages, tyrosine-phosphorylated SHPS-1 associates preferentially with SHP-1 (rather than SHP-2), implicating SHPS-1 as an inhibitory receptor scaffold in myeloid cells. Multiple SHPS-1 isoforms arise from differential glycosylation and alternative splicing.","method":"Co-immunoprecipitation from macrophage cell lines and peritoneal macrophages, immunoblotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP in primary macrophages, single lab, two orthogonal methods (co-IP + glycosylation analysis)","pmids":["9712903"],"is_preprint":false},{"year":1998,"finding":"Integrin-mediated cell adhesion to fibronectin/laminin induces tyrosine phosphorylation of SHPS-1 and its association with SHP-2; this requires both focal adhesion kinase (FAK) and Src-family kinases, but FAK does not directly phosphorylate SHPS-1's cytoplasmic domain in vitro. SHP-2 bound to SHPS-1 contributes to fibronectin-induced MAP kinase activation.","method":"In vitro phosphorylation assay, overexpression of Csk, FAK-deficient cells, MAP kinase activation assays, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple complementary genetic (FAK-null, Csk overexpression) and biochemical approaches in a single study","pmids":["9582366"],"is_preprint":false},{"year":1998,"finding":"Insulin induces tyrosine phosphorylation of SHPS-1 at Tyr449 and Tyr473; the N-terminal SH2 domain of SHP-2 preferentially binds pTyr449 and the C-terminal SH2 domain binds pTyr473, as shown by surface plasmon resonance with GST-SH2 fusion proteins. This SHPS-1–SHP-2 complex positively regulates insulin-induced MAP kinase activation.","method":"Site-directed mutagenesis, surface plasmon resonance, in vitro phosphatase assay, MAP kinase activation assay in CHO cells overexpressing insulin receptor","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis identifying specific phosphotyrosines, SPR quantifying SH2 binding, and in vitro phosphatase assay, multiple orthogonal methods in one study","pmids":["9535915"],"is_preprint":false},{"year":1998,"finding":"Growth hormone (GH) stimulates tyrosyl phosphorylation of SIRPalpha and enhances its association with SHP-2 via JAK2; co-expression of SIRPalpha and JAK2 in COS cells results in SIRPalpha tyrosyl phosphorylation and JAK2 association with SIRPalpha, placing SIRPA downstream of JAK2 in GH signaling.","method":"Co-immunoprecipitation, co-expression in COS cells, immunoblotting with phosphotyrosine antibodies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus co-expression reconstitution, single lab","pmids":["9507023"],"is_preprint":false},{"year":1998,"finding":"LPA-induced tyrosine phosphorylation of SHPS-1 and its association with SHP-2 requires RHO, FAK, and a Src-family kinase (demonstrated by C3 exoenzyme, FAK-deficient cells, and Csk overexpression).","method":"Inhibitor treatments (C3 exoenzyme, pertussis toxin), FAK-null cells, Csk overexpression, co-immunoprecipitation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic/pharmacological perturbations, single lab","pmids":["9662335"],"is_preprint":false},{"year":1999,"finding":"In adherent macrophages, SHPS-1 assembles two distinct multi-protein signaling complexes: one containing adaptor proteins SKAP55hom/R and FYB/SLAP-130 (whose recruitment requires SKAP55hom/R), and a second containing PYK2. Complex formation is independent of SHP-1 and SHPS-1 tyrosine phosphorylation but is regulated by integrin-mediated adhesion.","method":"Mass spectrometry identification, co-immunoprecipitation, immunoblotting in adherent macrophages","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification plus co-IP validation, single lab","pmids":["10469599"],"is_preprint":false},{"year":1999,"finding":"Neurotrophins NGF, BDNF, and NT-3 induce tyrosine phosphorylation of BIT/SIRPA and subsequent association with SHP-2, stimulating SHP-2 phosphatase activity, in PC12 cells and primary cultured neurons.","method":"Co-immunoprecipitation, immunoblotting, phosphatase activity assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional phosphatase assay, single lab","pmids":["10098842"],"is_preprint":false},{"year":2000,"finding":"CD47 was identified as the direct physiological ligand for SIRPA (rat OX41/SHPS-1) and human SIRPalpha1, with the membrane-distal V-like Ig domain of SIRPA sufficient for CD47 binding; the interaction was confirmed by surface plasmon resonance with purified recombinant proteins (Kd ~8 µM at 37°C).","method":"Affinity chromatography, peptide sequencing, surface plasmon resonance with purified recombinant proteins","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biophysical measurement with purified proteins via SPR, identified domain sufficient for binding, replicated across labs","pmids":["10940903"],"is_preprint":false},{"year":2000,"finding":"SHPS-1 extracellular (N-terminal Ig) domain mediates cell-cell adhesion via interaction with CD47 (demonstrated using CD47-null erythrocytes that fail to rosette on SHPS-1-expressing Ba/F3 cells); this interaction is independent of CD47-integrin association.","method":"Cell aggregation assay, anti-CD47 antibody blocking, CD47-null erythrocyte rosetting, truncation mutants","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (CD47-null) and antibody blocking with defined truncation mutants, single lab","pmids":["10725722"],"is_preprint":false},{"year":2000,"finding":"SHPS-1 mutant fibroblasts lacking the cytoplasmic domain show increased actin stress fiber and focal adhesion formation, enhanced spreading on fibronectin, defective polarized extension and migration, and reduced adhesion-induced Rho activation (but normal Rac activation), demonstrating that SHPS-1 cytoplasmic signaling regulates integrin-mediated cytoskeletal reorganization and cell motility through Rho.","method":"Fibroblast knock-in mutant mice (SHPS-1 cytoplasmic deletion), phalloidin staining, cell motility assay, Rho/Rac activity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined genetic model (cytoplasmic domain mutant knock-in) with multiple orthogonal phenotypic readouts and GTPase activation measurements, replicated in later work","pmids":["11118207"],"is_preprint":false},{"year":2000,"finding":"BIT/SHPS-1 enhances BDNF-promoted survival of cultured cerebral cortical neurons through a phosphatidylinositol 3-kinase–Akt pathway; this survival-enhancing effect does not require SHPS-1 tyrosine phosphorylation (4F mutant also effective), but Akt activation is enhanced by both wild-type and 4F SHPS-1.","method":"Recombinant adenovirus overexpression, PI3K inhibitor (LY294002), Akt phosphorylation immunoblotting, neuronal survival counting","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation-dead mutant plus pharmacological inhibitor, single lab","pmids":["10987830"],"is_preprint":false},{"year":2002,"finding":"Mice expressing an SHPS-1 mutant lacking most of the cytoplasmic region develop thrombocytopenia due to accelerated platelet clearance from the bloodstream, and peritoneal macrophages from these mice show enhanced phagocytosis of red blood cells with increased cell spreading and filopodia formation, demonstrating SHPS-1 cytoplasmic signaling negatively regulates macrophage phagocytic response and platelet survival.","method":"SHPS-1 cytoplasmic-deletion knock-in mice, platelet clearance assay, ex vivo phagocytosis assay, morphological analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined genetic knock-in model with in vivo and ex vivo phenotypic readouts, replicated in subsequent work","pmids":["12167615"],"is_preprint":false},{"year":2002,"finding":"A dominant-negative fragment of SHPS-1 cytoplasmic domain activates NF-κB and protects cells from TNF-induced apoptosis via Akt phosphorylation in a PI3K-dependent (wortmannin-sensitive), serum-dependent manner, suggesting full-length SIRPA negatively regulates NF-κB signaling.","method":"GSE retroviral library screen, NF-κB reporter assay, Akt phosphorylation immunoblotting, wortmannin inhibition","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppressor element approach with pharmacological validation, single lab","pmids":["12446684"],"is_preprint":false},{"year":2002,"finding":"SHPS-1 phosphorylation is required for SHP-2 recruitment to the plasma membrane after IGF-I stimulation; SHP-2 recruited to SHPS-1 is subsequently transferred to the IGF-I receptor to mediate receptor dephosphorylation. An SHPS-1 mutant unable to bind SHP-2 abrogates SHP-2 transfer and prolongs IGF-IR phosphorylation.","method":"SHPS-1 SHP-2 binding mutant expression, co-immunoprecipitation, catalytically inactive SHP-2, IGF-IR phosphorylation time-course in smooth muscle cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of both SHPS-1 and SHP-2 combined with receptor phosphorylation assays, multiple orthogonal approaches","pmids":["11779860"],"is_preprint":false},{"year":2003,"finding":"Engagement of SHPS-1 by CD47 (via CD47-Fc or anti-SHPS-1 antibodies) inhibits SHPS-1-promoted cell migration; this requires SHP-2 binding to the cytoplasmic domain (SHPS-1-4F mutant does not support migration and is insensitive to CD47 inhibition). CD47-SHPS-1 ligation causes dephosphorylation of SHPS-1, SHP-2 dissociation, and enhanced Rho activity/stress fiber formation.","method":"CD47-Fc ligand, anti-SHPS-1 antibodies, SHPS-1 phosphorylation mutant (4F), migration assays, Rho activity assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple ligand/antibody tools and defined phosphorylation mutant with functional migration and GTPase readouts","pmids":["12773380"],"is_preprint":false},{"year":2003,"finding":"CD47 binding to SHPS-1 (IAP-SHPS-1 interaction) is required for IGF-I-stimulated SHPS-1 phosphorylation, SHP-2 recruitment, and subsequent SHP-2 transfer to the IGF-I receptor in vascular smooth muscle cells; disrupting this interaction impairs IGF-I-stimulated MAPK activation, cell proliferation, and cell migration specifically (no effect on PDGF signaling).","method":"IAP monoclonal antibody blocking, mutant IAP that does not bind SHPS-1, co-immunoprecipitation, cell proliferation assay, migration assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — antibody blocking and genetic mutant with multiple functional readouts, ligand specificity controls, single lab","pmids":["12972543"],"is_preprint":false},{"year":2004,"finding":"The SHPS-1 ectodomain is shed from cells by a metalloproteinase at a juxtamembrane region; shedding is promoted by PKC activation or Ras, and the shed ectodomain has minimal CD47-binding activity. An SHPS-1 mutant resistant to shedding impairs cell migration, spreading, actin cytoskeleton reorganization, and increases paxillin and FAK tyrosine phosphorylation.","method":"In vitro metalloproteinase cleavage of SHPS-1-Fc, site mapping, metalloproteinase inhibitors, PKC activation, shedding-resistant mutant expression, migration/spreading assays, phospho-paxillin/FAK immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of metalloproteinase cleavage with site mapping plus functional gain-of-function mutant approach in cells","pmids":["15123722"],"is_preprint":false},{"year":2005,"finding":"Ligation of SHPS-1 on macrophages by CD47 on RBCs promotes SHPS-1 tyrosine phosphorylation and association with SHP-1, preventing FcγR-mediated disruption of the SHPS-1–SHP-1 complex and thereby inhibiting phagocytosis. This inhibition is mediated at the level of Syk or PI3K signaling (inhibitors of PI3K or Syk, but not MEK or Src, abolished the enhanced phagocytosis seen in SHPS-1 mutant macrophages).","method":"SHPS-1 cytoplasmic mutant mice, RNA interference knockdown, blocking antibodies, PI3K/Syk/MEK inhibitors, Syk/Cbl/FcRγ phosphorylation assays, phagocytosis assays with CD47-null RBCs","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — combined genetic (knock-in mutant, RNAi, CD47-null targets), pharmacological (inhibitors), and biochemical approaches in a single study","pmids":["15699129"],"is_preprint":false},{"year":2005,"finding":"SHPS-1 functions as an anchor protein that recruits both Shc and SHP-2 to the membrane upon IGF-I stimulation in vascular smooth muscle cells; Shc must associate with SHPS-1 (mediated partly by SHP-2 and Shc's polyproline sequence) for IGF-I-dependent Shc phosphorylation, which is required for sustained MAPK activation and cell proliferation.","method":"Cell-permeable inhibitory peptides (phospho-tyrosine binding motif, polyproline), SHPS-1 binding mutant, Shc proline-to-alanine mutant, co-immunoprecipitation, MAPK phosphorylation assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple peptide inhibitors and point mutants combined with co-IP and functional kinase assays in a single study","pmids":["15888547"],"is_preprint":false},{"year":2006,"finding":"Enhanced phagocytosis of CD47-deficient RBCs by splenic macrophages requires SHPS-1; in SHPS-1 mutant mice the clearance of CD47-null RBCs was minimal, and splenic macrophages from SHPS-1 mutant mice showed markedly reduced phagocytosis of CD47-null RBCs, revealing a role for SHPS-1 that extends beyond simply transducing the CD47 'don't eat me' signal.","method":"In vivo RBC clearance assay (transfusion of CD47-null RBCs into SHPS-1 mutant mice), ex vivo phagocytosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double-mutant genetic epistasis in vivo and ex vivo, single lab","pmids":["16580635"],"is_preprint":false},{"year":2007,"finding":"NOD-strain SIRPA binds human CD47 with enhanced affinity compared to other mouse strains, and this NOD-SIRPA expression on macrophages is required to support human hematopoietic engraftment in xenotransplantation models; polymorphism in the SIRPA IgV domain accounts for strain-specific differences in CD47 binding affinity.","method":"Positional genetics/backcross mapping, binding assays with recombinant proteins, macrophage depletion, xenotransplantation engraftment assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional genetics combined with binding assays and macrophage depletion functional experiments, replicated across labs","pmids":["17982459"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the murine SHPS-1 ligand-binding domain revealed an I2-set Ig fold resembling IgV antigen receptor domains with an extended C'E loop forming a dimer interface. Site-directed mutagenesis identified critical residues in the C'E loop and CDR-like regions required for CD47 binding, analogous to antigen receptor CDRs.","method":"X-ray crystallography, site-directed mutagenesis, CD47-binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis functional validation in a single study","pmids":["18045614"],"is_preprint":false},{"year":2007,"finding":"Three specific residues unique to the SIRPalpha D1 domain (absent in SIRPbeta) are critical for CD47 binding and independent of N-glycosylation; transferring these residues into SIRPbeta confers de novo CD47 binding. Epitope mapping identified a lateral binding region on the SIRPalpha Ig loop distinct from a previously proposed binding site.","method":"Site-directed mutagenesis, domain swapping between SIRPalpha and SIRPbeta, CD47-binding assays, homology modeling onto crystal structure, anti-SIRP antibody epitope mapping","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis plus domain-swapping with de novo gain-of-function validation, and structural mapping","pmids":["18025220"],"is_preprint":false},{"year":2008,"finding":"Surfactant proteins SP-A and SP-D directly bind SIRPA on alveolar macrophages and suppress apoptotic cell clearance (phagocytosis); this suppression is reversed by blocking SIRPA, inhibiting downstream SHP-1, or inhibiting RhoA/Rho kinase. Blocking SP-A/SP-D binding to SIRPA (using blocking antibodies or SIRPA mutant fibroblasts) confirmed the direct interaction.","method":"Macrophage phagocytosis assay, blocking antibodies, fibroblasts transfected with wild-type or mutant SIRPA, SHP-1-deficient mice, pharmacological inhibitors (sodium stibogluconate, Rho kinase inhibitor), chimeric mouse model","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding confirmed with blocking antibodies and SIRPA mutant transfectants; downstream pathway validated with SHP-1-null mice and pharmacological inhibitors across multiple models","pmids":["18420961"],"is_preprint":false},{"year":2008,"finding":"LPS and poly(I:C) induce tyrosine phosphorylation of SHPS-1 through a Src-family kinase and promote SHPS-1 association with SHP-1 and SHP-2; SHPS-1 then negatively regulates TLR4/TLR3-dependent TNF-α and IL-6 production by inhibiting NF-κB activation. An SHPS-1 phosphorylation mutant (4F) markedly promotes TLR-induced cytokine production.","method":"SHPS-1 4F phosphorylation mutant expression, CD8-cytoplasmic chimeric construct, NF-κB reporter assay, co-immunoprecipitation, cytokine ELISA, Src inhibitor","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphorylation mutant gain-of-function plus co-IP and NF-κB reporter, multiple orthogonal readouts","pmids":["18233962"],"is_preprint":false},{"year":2008,"finding":"Trans-interaction of CD47 and SHPS-1 at cell-cell contact sites results in endocytosis of the ligand-receptor complex (trans-endocytosis) mediated by clathrin and dynamin; a juxtamembrane region of SHPS-1 is indispensable, and Rac and Cdc42 regulate the process through actin cytoskeleton reorganization. Hippocampal neuron CD47 undergoes trans-endocytosis by neighboring astrocytes expressing SHPS-1.","method":"Trans-endocytosis assay in CHO cells, clathrin/dynamin inhibitors, dominant-negative Rac/Cdc42, SHPS-1 deletion mutants, live-cell imaging in primary neuron-astrocyte co-cultures","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological (clathrin/dynamin inhibitors), genetic (dominant-negative GTPases), structural (SHPS-1 deletion mutants) approaches combined with primary cell live imaging","pmids":["18349073"],"is_preprint":false},{"year":2008,"finding":"SIRP1alpha/SHPS-1 binds SHP2 upon IL-6 stimulation in a stimulation-dependent manner; cells expressing an intracellular SHPS-1 deletion mutant show enhanced SHP2 phosphorylation and ERK1/2 activation but delayed STAT3 activation and reduced STAT3-dependent gene induction, indicating SHPS-1 modulates IL-6 signaling through counteracting SHP2 phosphorylation to regulate ERK–STAT3 balance.","method":"SHPS-1 cytoplasmic deletion mutant MEFs, co-immunoprecipitation, ERK/STAT3 phosphorylation immunoblotting, STAT3 reporter gene assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant (cytoplasmic deletion) with co-IP and multiple signaling readouts, single lab","pmids":["18450421"],"is_preprint":false},{"year":2011,"finding":"CD47–SIRPA interaction on osteoclast precursors is required for osteoclastogenesis; disrupting CD47–SHPS-1 association markedly impairs osteoclast fusion (not differentiation) and is associated with lack of SHPS-1 phosphorylation, failure to recruit SHP-1, and no dephosphorylation of non-muscle myosin IIA. Cd47-null mice exhibit decreased bone mineral density and reduced trabecular bone volume.","method":"Cd47-null mice, IAP monoclonal antibody/mutant IAP disrupting CD47-SHPS-1, histomorphometry, osteoclast fusion assay, SHPS-1 phosphorylation, SHP-1 co-immunoprecipitation, myosin IIA phosphorylation assay","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mice combined with mechanistic pathway dissection (specific phosphorylation and phosphatase recruitment steps identified), multiple orthogonal methods","pmids":["21638321"],"is_preprint":false},{"year":2012,"finding":"SHPS-1 deficiency (cytoplasmic mutant) protects against ischemic brain damage by attenuating oxidative stress; the mutation suppresses phosphorylation of SHP-1 and SHP-2 while increasing Akt and GSK3β phosphorylation and upregulating Nrf2 and heme oxygenase-1, suggesting SIRPA normally inhibits the Akt–Nrf2 neuroprotective axis.","method":"SHPS-1 cytoplasmic mutant mice, middle cerebral artery occlusion model, infarct volume measurement, Akt/GSK3β/SHP-1/SHP-2 phosphorylation immunoblotting, Nrf2/HO-1 mRNA/protein quantification","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined genetic model with multiple signaling readouts, single lab, correlative pathway assignment","pmids":["22671569"],"is_preprint":false},{"year":2013,"finding":"The BALB/c-specific L29V SNP within the SIRPA IgV domain enhances binding affinity for human CD47 (intermediate between C57BL/6 and NOD SIRPA), and this increased affinity correlates with intermediate inhibition of macrophage phagocytosis of human hematopoietic stem cells, establishing that strain-specific SIRPA polymorphisms in the IgV domain directly modulate CD47 recognition and xenograft efficiency.","method":"Binding assays with strain-specific SIRPA proteins, in vitro phagocytosis assay against human HSCs, xenotransplantation engraftment, single nucleotide polymorphism analysis","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assay and phagocytosis assay linking specific SNP to function, single lab","pmids":["24269920"],"is_preprint":false},{"year":2020,"finding":"CD47 ligation repositions SIRPA to the phagocytic synapse where it becomes activated; at the synapse, SIRPA inhibits inside-out activation of integrin signaling to limit macrophage spreading across the target cell surface. Chemical reactivation of integrin (bypassing SIRPA inhibition) rescues phagocytosis similarly to a CD47 function-blocking antibody.","method":"Reconstituted phagocytic synapse system with defined signals, live-cell imaging of SIRPA localization, integrin activation assays, chemical integrin agonist bypass experiment","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted system with defined molecular components, live imaging of SIRPA repositioning, pharmacological bypass experiment, multiple orthogonal methods","pmids":["32768386"],"is_preprint":false},{"year":2017,"finding":"Treg cells protect dopaminergic neurons from MPP+ toxicity via direct cell-to-cell contact mediated by CD47 (on Tregs) binding SIRPA (on neurons); CD47 knockdown in Tregs or SIRPA knockdown in neurons abolishes neuroprotection. CD47–SIRPA interaction activates Rac1/Akt signaling in neurons, and inhibiting Rac1/Akt compromises neuroprotection.","method":"Live-cell imaging of CD47-Treg/SIRPA-neuron contact, siRNA knockdown, transwell co-culture controls, Rac1/Akt inhibitors, TH-immunoreactive cell counting","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown of both receptor and ligand plus pharmacological pathway dissection, single lab","pmids":["28268219"],"is_preprint":false},{"year":2023,"finding":"In osteosarcoma cells, SIRPA promotes metastasis by phosphorylating SP1 at Thr278 via ERK activation, protecting SP1 from proteasomal degradation; stabilized SP1 then transcriptionally induces SLC7A3 to increase arginine uptake, which further stabilizes SP1 in an ERK-independent manner ('SP1 stabilization circle'), facilitating cell migration.","method":"SIRPA knockdown and overexpression, co-immunoprecipitation, SP1 phosphorylation at Thr278 identification, proteasome inhibitor rescue, SLC7A3 promoter ChIP, arginine uptake assay, in vivo xenograft metastasis model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (co-IP, ChIP, phospho-site identification) plus in vivo validation, single lab","pmids":["37769797"],"is_preprint":false}],"current_model":"SIRPA (SHPS-1/SIRPα) is a transmembrane inhibitory receptor that, upon tyrosine phosphorylation of its cytoplasmic ITIMs by Src-family kinases, FAK, or JAK2 in response to growth factors, integrins, cytokines, or its ligand CD47, recruits and activates SHP-1 and SHP-2 phosphatases to form a membrane-proximal signaling scaffold; ligation of SIRPA by CD47 ('don't eat me' signal) repositions SIRPA to the phagocytic synapse where it inhibits integrin inside-out activation to block macrophage engulfment, with downstream effects also mediated through Rho GTPase regulation of cytoskeletal dynamics, cell migration, and cell survival via PI3K–Akt and NF-κB pathways."},"narrative":{"mechanistic_narrative":"SIRPA (SHPS-1/SIRPα) is a transmembrane glycoprotein with three extracellular Ig-like domains and four cytoplasmic YXX(L/V/I) motifs that operates as a tyrosine-phosphorylation-dependent docking platform coupling diverse extracellular cues to SHP-1/SHP-2 phosphatase signaling [PMID:8943344]. A broad range of stimuli — mitogens and integrin-mediated adhesion to fibronectin/laminin [PMID:8943344, PMID:9582366], insulin and IGF-I [PMID:9535915, PMID:11779860], growth hormone via JAK2 [PMID:9507023], LPA via Rho/FAK/Src [PMID:9662335], and neurotrophins [PMID:10098842] — drive phosphorylation of its cytoplasmic ITIM-like tyrosines (notably Tyr449 and Tyr473, bound by the N- and C-terminal SH2 domains of SHP-2 respectively), assembling a membrane-proximal scaffold [PMID:9535915]. In non-myeloid cells this complex tunes downstream signaling: SIRPA anchors SHP-2 and Shc at the membrane and transfers SHP-2 onto the IGF-I receptor to control receptor dephosphorylation, MAPK activation, proliferation and migration [PMID:11779860, PMID:15888547], and regulates cytoskeletal reorganization and motility through Rho, with cytoplasmic-domain-deficient cells showing excess stress fibers and impaired polarized migration [PMID:11118207]. The membrane-distal V-like Ig domain is the binding site for the physiological ligand CD47, an interaction mapped to an extended C'E loop and CDR-like regions and to residues unique to the SIRPα D1 domain [PMID:10940903, PMID:18045614, PMID:18025220]. In macrophages, tyrosine-phosphorylated SIRPA preferentially recruits SHP-1 [PMID:9712903], and CD47 ligation reinforces the SIRPA–SHP-1 complex to block FcγR-driven phagocytosis at the level of Syk/PI3K signaling, negatively regulating macrophage engulfment and platelet/erythrocyte survival in vivo [PMID:12167615, PMID:15699129]. Mechanistically, CD47 ligation repositions SIRPA to the phagocytic synapse where it inhibits inside-out integrin activation to limit macrophage spreading across the target [PMID:32768386]. SIRPA also restrains TLR3/TLR4-driven NF-κB activation and pro-inflammatory cytokine production [PMID:18233962], mediates trans-endocytosis of CD47–SIRPA complexes via clathrin/dynamin and Rac/Cdc42 [PMID:18349073], and supports CD47-dependent osteoclast fusion through SHP-1 recruitment and dephosphorylation of non-muscle myosin IIA [PMID:21638321]. Strain-specific polymorphisms in the SIRPA IgV domain set CD47-binding affinity and thereby determine the efficiency of human hematopoietic xenograft engraftment [PMID:17982459, PMID:24269920].","teleology":[{"year":1996,"claim":"Established SIRPA's core molecular identity: a multiply-tyrosine-phosphorylated transmembrane receptor that docks SHP-2, defining it as a phosphatase-recruiting scaffold rather than an enzyme itself.","evidence":"cDNA cloning, co-IP, and in vitro kinase assays from v-src-transformed fibroblasts","pmids":["8943344"],"confidence":"High","gaps":["Did not identify the physiological ligand","Did not establish cell-type-specific phosphatase preference"]},{"year":1998,"claim":"Defined the upstream activating cues and the phosphotyrosine code: integrin adhesion, insulin, GH, LPA and neurotrophins all phosphorylate SIRPA via Src-family kinases/FAK/JAK2, with specific tyrosines (Tyr449/Tyr473) engaging defined SHP-2 SH2 domains.","evidence":"Mutagenesis, surface plasmon resonance, FAK-null and Csk-overexpressing cells, MAP kinase assays across multiple stimuli","pmids":["9582366","9535915","9507023","9662335","9712903"],"confidence":"High","gaps":["Which kinase directly phosphorylates the cytoplasmic tyrosines in vivo remained unresolved (FAK does not act directly)","Did not unify how distinct stimuli converge on the same scaffold"]},{"year":2000,"claim":"Identified CD47 as the direct physiological ligand and mapped binding to the membrane-distal V-like Ig domain, converting SIRPA from an orphan scaffold into a defined cell-surface recognition receptor.","evidence":"Affinity purification, peptide sequencing, SPR with recombinant proteins, and CD47-null erythrocyte rosetting","pmids":["10940903","10725722"],"confidence":"High","gaps":["Low-micromolar affinity left the functional relevance of trans-interaction strength open","Did not resolve structural basis of binding"]},{"year":2000,"claim":"Demonstrated that SIRPA cytoplasmic signaling controls the actin cytoskeleton and cell motility through Rho, linking the scaffold to integrin-driven morphology.","evidence":"Cytoplasmic-deletion knock-in fibroblasts with phalloidin staining, motility assays, and Rho/Rac activity measurements","pmids":["11118207"],"confidence":"High","gaps":["How SIRPA couples to Rho regulators mechanistically was not defined","Did not connect this to phagocytosis at the time"]},{"year":2002,"claim":"Established SIRPA as a negative regulator of macrophage phagocytosis and platelet clearance in vivo, defining its myeloid inhibitory function.","evidence":"Cytoplasmic-deletion knock-in mice with platelet clearance and ex vivo erythrophagocytosis assays","pmids":["12167615"],"confidence":"High","gaps":["Did not pinpoint the inhibited phagocytic signaling node","Ligand dependence of the in vivo phenotype unresolved"]},{"year":2003,"claim":"Showed CD47 ligation acts as an off-switch: it dephosphorylates SIRPA, dissociates SHP-2, enhances Rho activity, and inhibits SIRPA-promoted migration, establishing ligand-controlled signaling reversal.","evidence":"CD47-Fc, anti-SIRPA antibodies, the 4F phosphorylation mutant, migration and Rho activity assays","pmids":["12773380","12972543"],"confidence":"High","gaps":["How CD47 binding triggers dephosphorylation mechanistically not resolved","Phosphatase responsible for SIRPA dephosphorylation not identified"]},{"year":2005,"claim":"Resolved the macrophage inhibitory mechanism: CD47 engagement stabilizes the SIRPA–SHP-1 complex against FcγR-induced disruption, blocking phagocytosis at the Syk/PI3K level.","evidence":"Mutant mice, RNAi, CD47-null target RBCs, and PI3K/Syk/MEK/Src inhibitors with Syk/Cbl/FcRγ phosphorylation readouts","pmids":["15699129"],"confidence":"High","gaps":["Did not establish how SHP-1 acts on Syk/PI3K substrates","Spatial organization of the inhibition was not addressed"]},{"year":2005,"claim":"Defined SIRPA's growth-factor scaffolding role: it anchors both SHP-2 and Shc and transfers SHP-2 to the IGF-I receptor, controlling sustained MAPK activation and proliferation.","evidence":"Inhibitory peptides, SIRPA and Shc point mutants, co-IP, and MAPK assays in vascular smooth muscle cells","pmids":["11779860","15888547"],"confidence":"High","gaps":["Generalizability beyond IGF-I/smooth muscle context not established","Stoichiometry of the SHP-2 transfer reaction unknown"]},{"year":2008,"claim":"Extended SIRPA's inhibitory reach to innate immunity and additional ligands: it restrains TLR3/TLR4 NF-κB and cytokine output, binds surfactant proteins SP-A/SP-D to suppress apoptotic-cell clearance, and mediates CD47 trans-endocytosis.","evidence":"4F mutant and CD8-chimera constructs, NF-κB reporters, blocking antibodies, SHP-1-null mice, Rho-kinase inhibitors, and clathrin/dynamin/dominant-negative GTPase trans-endocytosis assays","pmids":["18233962","18420961","18349073","18450421"],"confidence":"High","gaps":["How a single scaffold discriminates among CD47, SP-A/SP-D and signaling outputs not resolved","In vivo significance of trans-endocytosis incompletely defined"]},{"year":2007,"claim":"Solved the structural and species basis of CD47 recognition, identifying an I2-set Ig fold with an extended C'E loop and SIRPα-unique D1 residues, and explained strain-specific xenograft engraftment via IgV polymorphisms.","evidence":"X-ray crystallography, site-directed mutagenesis, domain swapping with SIRPβ, positional genetics, and xenotransplantation engraftment assays","pmids":["18045614","18025220","17982459","24269920"],"confidence":"High","gaps":["Did not co-crystallize the SIRPA–CD47 complex in these entries","Functional consequence of dimer interface in vivo unresolved"]},{"year":2011,"claim":"Showed CD47–SIRPA signaling drives osteoclast fusion through SHP-1 recruitment and myosin IIA dephosphorylation, broadening SIRPA function beyond phagocytic inhibition into cell-fusion/bone homeostasis.","evidence":"Cd47-null mice, IAP-blocking reagents, histomorphometry, fusion assays, and phosphorylation readouts","pmids":["21638321"],"confidence":"High","gaps":["Mechanistic link between SHP-1 and myosin IIA dephosphorylation not fully defined","Whether this requires phagocytic-synapse-like organization unknown"]},{"year":2020,"claim":"Provided the spatial mechanism of the 'don't eat me' signal: CD47 ligation repositions SIRPA to the phagocytic synapse where it blocks inside-out integrin activation, with integrin reactivation bypassing the inhibition.","evidence":"Reconstituted phagocytic synapse, live-cell imaging, integrin activation assays, and chemical integrin-agonist bypass","pmids":["32768386"],"confidence":"High","gaps":["How SHP-1/SHP-2 recruitment links to integrin inside-out inhibition step-by-step not fully resolved","Relative contribution of integrin versus other targets in vivo unquantified"]},{"year":2023,"claim":"Identified a cell-intrinsic pro-metastatic role in osteosarcoma whereby SIRPA drives ERK-dependent SP1 stabilization and an arginine-uptake feedback circuit, distinct from its canonical inhibitory receptor function.","evidence":"Knockdown/overexpression, co-IP, phospho-site mapping, ChIP, arginine-uptake assays, and xenograft metastasis model","pmids":["37769797"],"confidence":"Medium","gaps":["Single-lab finding awaiting independent confirmation","How SIRPA activates ERK in this context not mechanistically connected to its known scaffold tyrosines"]},{"year":null,"claim":"How SIRPA integrates its many distinct ligands and stimuli into context-specific SHP-1 versus SHP-2 outputs, and the precise enzymatic step linking phosphatase recruitment to integrin inside-out inhibition at the synapse, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model of stimulus-to-phosphatase selectivity","Direct kinase responsible for cytoplasmic tyrosine phosphorylation in vivo unsettled","Mechanistic chain from SHP recruitment to integrin regulation incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,8,31]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,14,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,15,18,25]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[9,26]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,14,31]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,18,25,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,14,27]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell 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In response to THBS1, involved in ROS signaling in non-phagocytic cells, stimulating NADPH oxidase-derived ROS production (PubMed:24511121)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P78324/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIRPA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":383,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIRPA","total_profiled":1310},"omim":[{"mim_id":"621323","title":"SIGNAL REGULATORY PROTEIN, BETA-2; SIRPB2","url":"https://www.omim.org/entry/621323"},{"mim_id":"606625","title":"SLAM FAMILY, MEMBER 7; SLAMF7","url":"https://www.omim.org/entry/606625"},{"mim_id":"605466","title":"SIGNAL REGULATORY PROTEIN, GAMMA; SIRPG","url":"https://www.omim.org/entry/605466"},{"mim_id":"602461","title":"SIGNAL REGULATORY PROTEIN, ALPHA; SIRPA","url":"https://www.omim.org/entry/602461"},{"mim_id":"600277","title":"INHIBITOR OF DNA BINDING 3; ID3","url":"https://www.omim.org/entry/600277"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":159.6}],"url":"https://www.proteinatlas.org/search/SIRPA"},"hgnc":{"alias_symbol":["SHPS1","SIRP","MYD-1","BIT","P84","SHPS-1","SIRPalpha","CD172a","SIRPalpha2","MFR","SIRP-ALPHA-1"],"prev_symbol":["PTPNS1"]},"alphafold":{"accession":"P78324","domains":[{"cath_id":"2.60.40.10","chopping":"37-146","consensus_level":"high","plddt":94.4111,"start":37,"end":146},{"cath_id":"2.60.40.10","chopping":"153-249","consensus_level":"high","plddt":96.5923,"start":153,"end":249},{"cath_id":"2.60.40.10","chopping":"256-348","consensus_level":"high","plddt":91.1392,"start":256,"end":348}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78324","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78324-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78324-F1-predicted_aligned_error_v6.png","plddt_mean":77.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIRPA","jax_strain_url":"https://www.jax.org/strain/search?query=SIRPA"},"sequence":{"accession":"P78324","fasta_url":"https://rest.uniprot.org/uniprotkb/P78324.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78324/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78324"}},"corpus_meta":[{"pmid":"22451913","id":"PMC_22451913","title":"The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22451913","citation_count":1371,"is_preprint":false},{"pmid":"21508972","id":"PMC_21508972","title":"Notch signalling in solid tumours: a little bit of everything but not all the time.","date":"2011","source":"Nature reviews. 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Multiple SHPS-1 isoforms arise from differential glycosylation and alternative splicing.\",\n      \"method\": \"Co-immunoprecipitation from macrophage cell lines and peritoneal macrophages, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP in primary macrophages, single lab, two orthogonal methods (co-IP + glycosylation analysis)\",\n      \"pmids\": [\"9712903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Integrin-mediated cell adhesion to fibronectin/laminin induces tyrosine phosphorylation of SHPS-1 and its association with SHP-2; this requires both focal adhesion kinase (FAK) and Src-family kinases, but FAK does not directly phosphorylate SHPS-1's cytoplasmic domain in vitro. SHP-2 bound to SHPS-1 contributes to fibronectin-induced MAP kinase activation.\",\n      \"method\": \"In vitro phosphorylation assay, overexpression of Csk, FAK-deficient cells, MAP kinase activation assays, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple complementary genetic (FAK-null, Csk overexpression) and biochemical approaches in a single study\",\n      \"pmids\": [\"9582366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Insulin induces tyrosine phosphorylation of SHPS-1 at Tyr449 and Tyr473; the N-terminal SH2 domain of SHP-2 preferentially binds pTyr449 and the C-terminal SH2 domain binds pTyr473, as shown by surface plasmon resonance with GST-SH2 fusion proteins. This SHPS-1–SHP-2 complex positively regulates insulin-induced MAP kinase activation.\",\n      \"method\": \"Site-directed mutagenesis, surface plasmon resonance, in vitro phosphatase assay, MAP kinase activation assay in CHO cells overexpressing insulin receptor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis identifying specific phosphotyrosines, SPR quantifying SH2 binding, and in vitro phosphatase assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9535915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Growth hormone (GH) stimulates tyrosyl phosphorylation of SIRPalpha and enhances its association with SHP-2 via JAK2; co-expression of SIRPalpha and JAK2 in COS cells results in SIRPalpha tyrosyl phosphorylation and JAK2 association with SIRPalpha, placing SIRPA downstream of JAK2 in GH signaling.\",\n      \"method\": \"Co-immunoprecipitation, co-expression in COS cells, immunoblotting with phosphotyrosine antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus co-expression reconstitution, single lab\",\n      \"pmids\": [\"9507023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"LPA-induced tyrosine phosphorylation of SHPS-1 and its association with SHP-2 requires RHO, FAK, and a Src-family kinase (demonstrated by C3 exoenzyme, FAK-deficient cells, and Csk overexpression).\",\n      \"method\": \"Inhibitor treatments (C3 exoenzyme, pertussis toxin), FAK-null cells, Csk overexpression, co-immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic/pharmacological perturbations, single lab\",\n      \"pmids\": [\"9662335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In adherent macrophages, SHPS-1 assembles two distinct multi-protein signaling complexes: one containing adaptor proteins SKAP55hom/R and FYB/SLAP-130 (whose recruitment requires SKAP55hom/R), and a second containing PYK2. Complex formation is independent of SHP-1 and SHPS-1 tyrosine phosphorylation but is regulated by integrin-mediated adhesion.\",\n      \"method\": \"Mass spectrometry identification, co-immunoprecipitation, immunoblotting in adherent macrophages\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus co-IP validation, single lab\",\n      \"pmids\": [\"10469599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Neurotrophins NGF, BDNF, and NT-3 induce tyrosine phosphorylation of BIT/SIRPA and subsequent association with SHP-2, stimulating SHP-2 phosphatase activity, in PC12 cells and primary cultured neurons.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting, phosphatase activity assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional phosphatase assay, single lab\",\n      \"pmids\": [\"10098842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD47 was identified as the direct physiological ligand for SIRPA (rat OX41/SHPS-1) and human SIRPalpha1, with the membrane-distal V-like Ig domain of SIRPA sufficient for CD47 binding; the interaction was confirmed by surface plasmon resonance with purified recombinant proteins (Kd ~8 µM at 37°C).\",\n      \"method\": \"Affinity chromatography, peptide sequencing, surface plasmon resonance with purified recombinant proteins\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biophysical measurement with purified proteins via SPR, identified domain sufficient for binding, replicated across labs\",\n      \"pmids\": [\"10940903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHPS-1 extracellular (N-terminal Ig) domain mediates cell-cell adhesion via interaction with CD47 (demonstrated using CD47-null erythrocytes that fail to rosette on SHPS-1-expressing Ba/F3 cells); this interaction is independent of CD47-integrin association.\",\n      \"method\": \"Cell aggregation assay, anti-CD47 antibody blocking, CD47-null erythrocyte rosetting, truncation mutants\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (CD47-null) and antibody blocking with defined truncation mutants, single lab\",\n      \"pmids\": [\"10725722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHPS-1 mutant fibroblasts lacking the cytoplasmic domain show increased actin stress fiber and focal adhesion formation, enhanced spreading on fibronectin, defective polarized extension and migration, and reduced adhesion-induced Rho activation (but normal Rac activation), demonstrating that SHPS-1 cytoplasmic signaling regulates integrin-mediated cytoskeletal reorganization and cell motility through Rho.\",\n      \"method\": \"Fibroblast knock-in mutant mice (SHPS-1 cytoplasmic deletion), phalloidin staining, cell motility assay, Rho/Rac activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined genetic model (cytoplasmic domain mutant knock-in) with multiple orthogonal phenotypic readouts and GTPase activation measurements, replicated in later work\",\n      \"pmids\": [\"11118207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"BIT/SHPS-1 enhances BDNF-promoted survival of cultured cerebral cortical neurons through a phosphatidylinositol 3-kinase–Akt pathway; this survival-enhancing effect does not require SHPS-1 tyrosine phosphorylation (4F mutant also effective), but Akt activation is enhanced by both wild-type and 4F SHPS-1.\",\n      \"method\": \"Recombinant adenovirus overexpression, PI3K inhibitor (LY294002), Akt phosphorylation immunoblotting, neuronal survival counting\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation-dead mutant plus pharmacological inhibitor, single lab\",\n      \"pmids\": [\"10987830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mice expressing an SHPS-1 mutant lacking most of the cytoplasmic region develop thrombocytopenia due to accelerated platelet clearance from the bloodstream, and peritoneal macrophages from these mice show enhanced phagocytosis of red blood cells with increased cell spreading and filopodia formation, demonstrating SHPS-1 cytoplasmic signaling negatively regulates macrophage phagocytic response and platelet survival.\",\n      \"method\": \"SHPS-1 cytoplasmic-deletion knock-in mice, platelet clearance assay, ex vivo phagocytosis assay, morphological analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined genetic knock-in model with in vivo and ex vivo phenotypic readouts, replicated in subsequent work\",\n      \"pmids\": [\"12167615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A dominant-negative fragment of SHPS-1 cytoplasmic domain activates NF-κB and protects cells from TNF-induced apoptosis via Akt phosphorylation in a PI3K-dependent (wortmannin-sensitive), serum-dependent manner, suggesting full-length SIRPA negatively regulates NF-κB signaling.\",\n      \"method\": \"GSE retroviral library screen, NF-κB reporter assay, Akt phosphorylation immunoblotting, wortmannin inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppressor element approach with pharmacological validation, single lab\",\n      \"pmids\": [\"12446684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SHPS-1 phosphorylation is required for SHP-2 recruitment to the plasma membrane after IGF-I stimulation; SHP-2 recruited to SHPS-1 is subsequently transferred to the IGF-I receptor to mediate receptor dephosphorylation. An SHPS-1 mutant unable to bind SHP-2 abrogates SHP-2 transfer and prolongs IGF-IR phosphorylation.\",\n      \"method\": \"SHPS-1 SHP-2 binding mutant expression, co-immunoprecipitation, catalytically inactive SHP-2, IGF-IR phosphorylation time-course in smooth muscle cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of both SHPS-1 and SHP-2 combined with receptor phosphorylation assays, multiple orthogonal approaches\",\n      \"pmids\": [\"11779860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Engagement of SHPS-1 by CD47 (via CD47-Fc or anti-SHPS-1 antibodies) inhibits SHPS-1-promoted cell migration; this requires SHP-2 binding to the cytoplasmic domain (SHPS-1-4F mutant does not support migration and is insensitive to CD47 inhibition). CD47-SHPS-1 ligation causes dephosphorylation of SHPS-1, SHP-2 dissociation, and enhanced Rho activity/stress fiber formation.\",\n      \"method\": \"CD47-Fc ligand, anti-SHPS-1 antibodies, SHPS-1 phosphorylation mutant (4F), migration assays, Rho activity assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple ligand/antibody tools and defined phosphorylation mutant with functional migration and GTPase readouts\",\n      \"pmids\": [\"12773380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD47 binding to SHPS-1 (IAP-SHPS-1 interaction) is required for IGF-I-stimulated SHPS-1 phosphorylation, SHP-2 recruitment, and subsequent SHP-2 transfer to the IGF-I receptor in vascular smooth muscle cells; disrupting this interaction impairs IGF-I-stimulated MAPK activation, cell proliferation, and cell migration specifically (no effect on PDGF signaling).\",\n      \"method\": \"IAP monoclonal antibody blocking, mutant IAP that does not bind SHPS-1, co-immunoprecipitation, cell proliferation assay, migration assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antibody blocking and genetic mutant with multiple functional readouts, ligand specificity controls, single lab\",\n      \"pmids\": [\"12972543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The SHPS-1 ectodomain is shed from cells by a metalloproteinase at a juxtamembrane region; shedding is promoted by PKC activation or Ras, and the shed ectodomain has minimal CD47-binding activity. An SHPS-1 mutant resistant to shedding impairs cell migration, spreading, actin cytoskeleton reorganization, and increases paxillin and FAK tyrosine phosphorylation.\",\n      \"method\": \"In vitro metalloproteinase cleavage of SHPS-1-Fc, site mapping, metalloproteinase inhibitors, PKC activation, shedding-resistant mutant expression, migration/spreading assays, phospho-paxillin/FAK immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of metalloproteinase cleavage with site mapping plus functional gain-of-function mutant approach in cells\",\n      \"pmids\": [\"15123722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ligation of SHPS-1 on macrophages by CD47 on RBCs promotes SHPS-1 tyrosine phosphorylation and association with SHP-1, preventing FcγR-mediated disruption of the SHPS-1–SHP-1 complex and thereby inhibiting phagocytosis. This inhibition is mediated at the level of Syk or PI3K signaling (inhibitors of PI3K or Syk, but not MEK or Src, abolished the enhanced phagocytosis seen in SHPS-1 mutant macrophages).\",\n      \"method\": \"SHPS-1 cytoplasmic mutant mice, RNA interference knockdown, blocking antibodies, PI3K/Syk/MEK inhibitors, Syk/Cbl/FcRγ phosphorylation assays, phagocytosis assays with CD47-null RBCs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — combined genetic (knock-in mutant, RNAi, CD47-null targets), pharmacological (inhibitors), and biochemical approaches in a single study\",\n      \"pmids\": [\"15699129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SHPS-1 functions as an anchor protein that recruits both Shc and SHP-2 to the membrane upon IGF-I stimulation in vascular smooth muscle cells; Shc must associate with SHPS-1 (mediated partly by SHP-2 and Shc's polyproline sequence) for IGF-I-dependent Shc phosphorylation, which is required for sustained MAPK activation and cell proliferation.\",\n      \"method\": \"Cell-permeable inhibitory peptides (phospho-tyrosine binding motif, polyproline), SHPS-1 binding mutant, Shc proline-to-alanine mutant, co-immunoprecipitation, MAPK phosphorylation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple peptide inhibitors and point mutants combined with co-IP and functional kinase assays in a single study\",\n      \"pmids\": [\"15888547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Enhanced phagocytosis of CD47-deficient RBCs by splenic macrophages requires SHPS-1; in SHPS-1 mutant mice the clearance of CD47-null RBCs was minimal, and splenic macrophages from SHPS-1 mutant mice showed markedly reduced phagocytosis of CD47-null RBCs, revealing a role for SHPS-1 that extends beyond simply transducing the CD47 'don't eat me' signal.\",\n      \"method\": \"In vivo RBC clearance assay (transfusion of CD47-null RBCs into SHPS-1 mutant mice), ex vivo phagocytosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-mutant genetic epistasis in vivo and ex vivo, single lab\",\n      \"pmids\": [\"16580635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NOD-strain SIRPA binds human CD47 with enhanced affinity compared to other mouse strains, and this NOD-SIRPA expression on macrophages is required to support human hematopoietic engraftment in xenotransplantation models; polymorphism in the SIRPA IgV domain accounts for strain-specific differences in CD47 binding affinity.\",\n      \"method\": \"Positional genetics/backcross mapping, binding assays with recombinant proteins, macrophage depletion, xenotransplantation engraftment assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional genetics combined with binding assays and macrophage depletion functional experiments, replicated across labs\",\n      \"pmids\": [\"17982459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the murine SHPS-1 ligand-binding domain revealed an I2-set Ig fold resembling IgV antigen receptor domains with an extended C'E loop forming a dimer interface. Site-directed mutagenesis identified critical residues in the C'E loop and CDR-like regions required for CD47 binding, analogous to antigen receptor CDRs.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, CD47-binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis functional validation in a single study\",\n      \"pmids\": [\"18045614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Three specific residues unique to the SIRPalpha D1 domain (absent in SIRPbeta) are critical for CD47 binding and independent of N-glycosylation; transferring these residues into SIRPbeta confers de novo CD47 binding. Epitope mapping identified a lateral binding region on the SIRPalpha Ig loop distinct from a previously proposed binding site.\",\n      \"method\": \"Site-directed mutagenesis, domain swapping between SIRPalpha and SIRPbeta, CD47-binding assays, homology modeling onto crystal structure, anti-SIRP antibody epitope mapping\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis plus domain-swapping with de novo gain-of-function validation, and structural mapping\",\n      \"pmids\": [\"18025220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Surfactant proteins SP-A and SP-D directly bind SIRPA on alveolar macrophages and suppress apoptotic cell clearance (phagocytosis); this suppression is reversed by blocking SIRPA, inhibiting downstream SHP-1, or inhibiting RhoA/Rho kinase. Blocking SP-A/SP-D binding to SIRPA (using blocking antibodies or SIRPA mutant fibroblasts) confirmed the direct interaction.\",\n      \"method\": \"Macrophage phagocytosis assay, blocking antibodies, fibroblasts transfected with wild-type or mutant SIRPA, SHP-1-deficient mice, pharmacological inhibitors (sodium stibogluconate, Rho kinase inhibitor), chimeric mouse model\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding confirmed with blocking antibodies and SIRPA mutant transfectants; downstream pathway validated with SHP-1-null mice and pharmacological inhibitors across multiple models\",\n      \"pmids\": [\"18420961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LPS and poly(I:C) induce tyrosine phosphorylation of SHPS-1 through a Src-family kinase and promote SHPS-1 association with SHP-1 and SHP-2; SHPS-1 then negatively regulates TLR4/TLR3-dependent TNF-α and IL-6 production by inhibiting NF-κB activation. An SHPS-1 phosphorylation mutant (4F) markedly promotes TLR-induced cytokine production.\",\n      \"method\": \"SHPS-1 4F phosphorylation mutant expression, CD8-cytoplasmic chimeric construct, NF-κB reporter assay, co-immunoprecipitation, cytokine ELISA, Src inhibitor\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphorylation mutant gain-of-function plus co-IP and NF-κB reporter, multiple orthogonal readouts\",\n      \"pmids\": [\"18233962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Trans-interaction of CD47 and SHPS-1 at cell-cell contact sites results in endocytosis of the ligand-receptor complex (trans-endocytosis) mediated by clathrin and dynamin; a juxtamembrane region of SHPS-1 is indispensable, and Rac and Cdc42 regulate the process through actin cytoskeleton reorganization. Hippocampal neuron CD47 undergoes trans-endocytosis by neighboring astrocytes expressing SHPS-1.\",\n      \"method\": \"Trans-endocytosis assay in CHO cells, clathrin/dynamin inhibitors, dominant-negative Rac/Cdc42, SHPS-1 deletion mutants, live-cell imaging in primary neuron-astrocyte co-cultures\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological (clathrin/dynamin inhibitors), genetic (dominant-negative GTPases), structural (SHPS-1 deletion mutants) approaches combined with primary cell live imaging\",\n      \"pmids\": [\"18349073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SIRP1alpha/SHPS-1 binds SHP2 upon IL-6 stimulation in a stimulation-dependent manner; cells expressing an intracellular SHPS-1 deletion mutant show enhanced SHP2 phosphorylation and ERK1/2 activation but delayed STAT3 activation and reduced STAT3-dependent gene induction, indicating SHPS-1 modulates IL-6 signaling through counteracting SHP2 phosphorylation to regulate ERK–STAT3 balance.\",\n      \"method\": \"SHPS-1 cytoplasmic deletion mutant MEFs, co-immunoprecipitation, ERK/STAT3 phosphorylation immunoblotting, STAT3 reporter gene assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant (cytoplasmic deletion) with co-IP and multiple signaling readouts, single lab\",\n      \"pmids\": [\"18450421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD47–SIRPA interaction on osteoclast precursors is required for osteoclastogenesis; disrupting CD47–SHPS-1 association markedly impairs osteoclast fusion (not differentiation) and is associated with lack of SHPS-1 phosphorylation, failure to recruit SHP-1, and no dephosphorylation of non-muscle myosin IIA. Cd47-null mice exhibit decreased bone mineral density and reduced trabecular bone volume.\",\n      \"method\": \"Cd47-null mice, IAP monoclonal antibody/mutant IAP disrupting CD47-SHPS-1, histomorphometry, osteoclast fusion assay, SHPS-1 phosphorylation, SHP-1 co-immunoprecipitation, myosin IIA phosphorylation assay\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mice combined with mechanistic pathway dissection (specific phosphorylation and phosphatase recruitment steps identified), multiple orthogonal methods\",\n      \"pmids\": [\"21638321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SHPS-1 deficiency (cytoplasmic mutant) protects against ischemic brain damage by attenuating oxidative stress; the mutation suppresses phosphorylation of SHP-1 and SHP-2 while increasing Akt and GSK3β phosphorylation and upregulating Nrf2 and heme oxygenase-1, suggesting SIRPA normally inhibits the Akt–Nrf2 neuroprotective axis.\",\n      \"method\": \"SHPS-1 cytoplasmic mutant mice, middle cerebral artery occlusion model, infarct volume measurement, Akt/GSK3β/SHP-1/SHP-2 phosphorylation immunoblotting, Nrf2/HO-1 mRNA/protein quantification\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic model with multiple signaling readouts, single lab, correlative pathway assignment\",\n      \"pmids\": [\"22671569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The BALB/c-specific L29V SNP within the SIRPA IgV domain enhances binding affinity for human CD47 (intermediate between C57BL/6 and NOD SIRPA), and this increased affinity correlates with intermediate inhibition of macrophage phagocytosis of human hematopoietic stem cells, establishing that strain-specific SIRPA polymorphisms in the IgV domain directly modulate CD47 recognition and xenograft efficiency.\",\n      \"method\": \"Binding assays with strain-specific SIRPA proteins, in vitro phagocytosis assay against human HSCs, xenotransplantation engraftment, single nucleotide polymorphism analysis\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assay and phagocytosis assay linking specific SNP to function, single lab\",\n      \"pmids\": [\"24269920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD47 ligation repositions SIRPA to the phagocytic synapse where it becomes activated; at the synapse, SIRPA inhibits inside-out activation of integrin signaling to limit macrophage spreading across the target cell surface. Chemical reactivation of integrin (bypassing SIRPA inhibition) rescues phagocytosis similarly to a CD47 function-blocking antibody.\",\n      \"method\": \"Reconstituted phagocytic synapse system with defined signals, live-cell imaging of SIRPA localization, integrin activation assays, chemical integrin agonist bypass experiment\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted system with defined molecular components, live imaging of SIRPA repositioning, pharmacological bypass experiment, multiple orthogonal methods\",\n      \"pmids\": [\"32768386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Treg cells protect dopaminergic neurons from MPP+ toxicity via direct cell-to-cell contact mediated by CD47 (on Tregs) binding SIRPA (on neurons); CD47 knockdown in Tregs or SIRPA knockdown in neurons abolishes neuroprotection. CD47–SIRPA interaction activates Rac1/Akt signaling in neurons, and inhibiting Rac1/Akt compromises neuroprotection.\",\n      \"method\": \"Live-cell imaging of CD47-Treg/SIRPA-neuron contact, siRNA knockdown, transwell co-culture controls, Rac1/Akt inhibitors, TH-immunoreactive cell counting\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown of both receptor and ligand plus pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"28268219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In osteosarcoma cells, SIRPA promotes metastasis by phosphorylating SP1 at Thr278 via ERK activation, protecting SP1 from proteasomal degradation; stabilized SP1 then transcriptionally induces SLC7A3 to increase arginine uptake, which further stabilizes SP1 in an ERK-independent manner ('SP1 stabilization circle'), facilitating cell migration.\",\n      \"method\": \"SIRPA knockdown and overexpression, co-immunoprecipitation, SP1 phosphorylation at Thr278 identification, proteasome inhibitor rescue, SLC7A3 promoter ChIP, arginine uptake assay, in vivo xenograft metastasis model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (co-IP, ChIP, phospho-site identification) plus in vivo validation, single lab\",\n      \"pmids\": [\"37769797\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRPA (SHPS-1/SIRPα) is a transmembrane inhibitory receptor that, upon tyrosine phosphorylation of its cytoplasmic ITIMs by Src-family kinases, FAK, or JAK2 in response to growth factors, integrins, cytokines, or its ligand CD47, recruits and activates SHP-1 and SHP-2 phosphatases to form a membrane-proximal signaling scaffold; ligation of SIRPA by CD47 ('don't eat me' signal) repositions SIRPA to the phagocytic synapse where it inhibits integrin inside-out activation to block macrophage engulfment, with downstream effects also mediated through Rho GTPase regulation of cytoskeletal dynamics, cell migration, and cell survival via PI3K–Akt and NF-κB pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIRPA (SHPS-1/SIRPα) is a transmembrane glycoprotein with three extracellular Ig-like domains and four cytoplasmic YXX(L/V/I) motifs that operates as a tyrosine-phosphorylation-dependent docking platform coupling diverse extracellular cues to SHP-1/SHP-2 phosphatase signaling [#0]. A broad range of stimuli — mitogens and integrin-mediated adhesion to fibronectin/laminin [#0, #2], insulin and IGF-I [#3, #14], growth hormone via JAK2 [#4], LPA via Rho/FAK/Src [#5], and neurotrophins [#7] — drive phosphorylation of its cytoplasmic ITIM-like tyrosines (notably Tyr449 and Tyr473, bound by the N- and C-terminal SH2 domains of SHP-2 respectively), assembling a membrane-proximal scaffold [#3]. In non-myeloid cells this complex tunes downstream signaling: SIRPA anchors SHP-2 and Shc at the membrane and transfers SHP-2 onto the IGF-I receptor to control receptor dephosphorylation, MAPK activation, proliferation and migration [#14, #19], and regulates cytoskeletal reorganization and motility through Rho, with cytoplasmic-domain-deficient cells showing excess stress fibers and impaired polarized migration [#10]. The membrane-distal V-like Ig domain is the binding site for the physiological ligand CD47, an interaction mapped to an extended C'E loop and CDR-like regions and to residues unique to the SIRPα D1 domain [#8, #22, #23]. In macrophages, tyrosine-phosphorylated SIRPA preferentially recruits SHP-1 [#1], and CD47 ligation reinforces the SIRPA–SHP-1 complex to block FcγR-driven phagocytosis at the level of Syk/PI3K signaling, negatively regulating macrophage engulfment and platelet/erythrocyte survival in vivo [#12, #18]. Mechanistically, CD47 ligation repositions SIRPA to the phagocytic synapse where it inhibits inside-out integrin activation to limit macrophage spreading across the target [#31]. SIRPA also restrains TLR3/TLR4-driven NF-κB activation and pro-inflammatory cytokine production [#25], mediates trans-endocytosis of CD47–SIRPA complexes via clathrin/dynamin and Rac/Cdc42 [#26], and supports CD47-dependent osteoclast fusion through SHP-1 recruitment and dephosphorylation of non-muscle myosin IIA [#28]. Strain-specific polymorphisms in the SIRPA IgV domain set CD47-binding affinity and thereby determine the efficiency of human hematopoietic xenograft engraftment [#21, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established SIRPA's core molecular identity: a multiply-tyrosine-phosphorylated transmembrane receptor that docks SHP-2, defining it as a phosphatase-recruiting scaffold rather than an enzyme itself.\",\n      \"evidence\": \"cDNA cloning, co-IP, and in vitro kinase assays from v-src-transformed fibroblasts\",\n      \"pmids\": [\"8943344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the physiological ligand\", \"Did not establish cell-type-specific phosphatase preference\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the upstream activating cues and the phosphotyrosine code: integrin adhesion, insulin, GH, LPA and neurotrophins all phosphorylate SIRPA via Src-family kinases/FAK/JAK2, with specific tyrosines (Tyr449/Tyr473) engaging defined SHP-2 SH2 domains.\",\n      \"evidence\": \"Mutagenesis, surface plasmon resonance, FAK-null and Csk-overexpressing cells, MAP kinase assays across multiple stimuli\",\n      \"pmids\": [\"9582366\", \"9535915\", \"9507023\", \"9662335\", \"9712903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which kinase directly phosphorylates the cytoplasmic tyrosines in vivo remained unresolved (FAK does not act directly)\", \"Did not unify how distinct stimuli converge on the same scaffold\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified CD47 as the direct physiological ligand and mapped binding to the membrane-distal V-like Ig domain, converting SIRPA from an orphan scaffold into a defined cell-surface recognition receptor.\",\n      \"evidence\": \"Affinity purification, peptide sequencing, SPR with recombinant proteins, and CD47-null erythrocyte rosetting\",\n      \"pmids\": [\"10940903\", \"10725722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Low-micromolar affinity left the functional relevance of trans-interaction strength open\", \"Did not resolve structural basis of binding\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that SIRPA cytoplasmic signaling controls the actin cytoskeleton and cell motility through Rho, linking the scaffold to integrin-driven morphology.\",\n      \"evidence\": \"Cytoplasmic-deletion knock-in fibroblasts with phalloidin staining, motility assays, and Rho/Rac activity measurements\",\n      \"pmids\": [\"11118207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SIRPA couples to Rho regulators mechanistically was not defined\", \"Did not connect this to phagocytosis at the time\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SIRPA as a negative regulator of macrophage phagocytosis and platelet clearance in vivo, defining its myeloid inhibitory function.\",\n      \"evidence\": \"Cytoplasmic-deletion knock-in mice with platelet clearance and ex vivo erythrophagocytosis assays\",\n      \"pmids\": [\"12167615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not pinpoint the inhibited phagocytic signaling node\", \"Ligand dependence of the in vivo phenotype unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed CD47 ligation acts as an off-switch: it dephosphorylates SIRPA, dissociates SHP-2, enhances Rho activity, and inhibits SIRPA-promoted migration, establishing ligand-controlled signaling reversal.\",\n      \"evidence\": \"CD47-Fc, anti-SIRPA antibodies, the 4F phosphorylation mutant, migration and Rho activity assays\",\n      \"pmids\": [\"12773380\", \"12972543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD47 binding triggers dephosphorylation mechanistically not resolved\", \"Phosphatase responsible for SIRPA dephosphorylation not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the macrophage inhibitory mechanism: CD47 engagement stabilizes the SIRPA–SHP-1 complex against FcγR-induced disruption, blocking phagocytosis at the Syk/PI3K level.\",\n      \"evidence\": \"Mutant mice, RNAi, CD47-null target RBCs, and PI3K/Syk/MEK/Src inhibitors with Syk/Cbl/FcRγ phosphorylation readouts\",\n      \"pmids\": [\"15699129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how SHP-1 acts on Syk/PI3K substrates\", \"Spatial organization of the inhibition was not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined SIRPA's growth-factor scaffolding role: it anchors both SHP-2 and Shc and transfers SHP-2 to the IGF-I receptor, controlling sustained MAPK activation and proliferation.\",\n      \"evidence\": \"Inhibitory peptides, SIRPA and Shc point mutants, co-IP, and MAPK assays in vascular smooth muscle cells\",\n      \"pmids\": [\"11779860\", \"15888547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability beyond IGF-I/smooth muscle context not established\", \"Stoichiometry of the SHP-2 transfer reaction unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended SIRPA's inhibitory reach to innate immunity and additional ligands: it restrains TLR3/TLR4 NF-κB and cytokine output, binds surfactant proteins SP-A/SP-D to suppress apoptotic-cell clearance, and mediates CD47 trans-endocytosis.\",\n      \"evidence\": \"4F mutant and CD8-chimera constructs, NF-κB reporters, blocking antibodies, SHP-1-null mice, Rho-kinase inhibitors, and clathrin/dynamin/dominant-negative GTPase trans-endocytosis assays\",\n      \"pmids\": [\"18233962\", \"18420961\", \"18349073\", \"18450421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single scaffold discriminates among CD47, SP-A/SP-D and signaling outputs not resolved\", \"In vivo significance of trans-endocytosis incompletely defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Solved the structural and species basis of CD47 recognition, identifying an I2-set Ig fold with an extended C'E loop and SIRPα-unique D1 residues, and explained strain-specific xenograft engraftment via IgV polymorphisms.\",\n      \"evidence\": \"X-ray crystallography, site-directed mutagenesis, domain swapping with SIRPβ, positional genetics, and xenotransplantation engraftment assays\",\n      \"pmids\": [\"18045614\", \"18025220\", \"17982459\", \"24269920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not co-crystallize the SIRPA–CD47 complex in these entries\", \"Functional consequence of dimer interface in vivo unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CD47–SIRPA signaling drives osteoclast fusion through SHP-1 recruitment and myosin IIA dephosphorylation, broadening SIRPA function beyond phagocytic inhibition into cell-fusion/bone homeostasis.\",\n      \"evidence\": \"Cd47-null mice, IAP-blocking reagents, histomorphometry, fusion assays, and phosphorylation readouts\",\n      \"pmids\": [\"21638321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between SHP-1 and myosin IIA dephosphorylation not fully defined\", \"Whether this requires phagocytic-synapse-like organization unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the spatial mechanism of the 'don't eat me' signal: CD47 ligation repositions SIRPA to the phagocytic synapse where it blocks inside-out integrin activation, with integrin reactivation bypassing the inhibition.\",\n      \"evidence\": \"Reconstituted phagocytic synapse, live-cell imaging, integrin activation assays, and chemical integrin-agonist bypass\",\n      \"pmids\": [\"32768386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SHP-1/SHP-2 recruitment links to integrin inside-out inhibition step-by-step not fully resolved\", \"Relative contribution of integrin versus other targets in vivo unquantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a cell-intrinsic pro-metastatic role in osteosarcoma whereby SIRPA drives ERK-dependent SP1 stabilization and an arginine-uptake feedback circuit, distinct from its canonical inhibitory receptor function.\",\n      \"evidence\": \"Knockdown/overexpression, co-IP, phospho-site mapping, ChIP, arginine-uptake assays, and xenograft metastasis model\",\n      \"pmids\": [\"37769797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding awaiting independent confirmation\", \"How SIRPA activates ERK in this context not mechanistically connected to its known scaffold tyrosines\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIRPA integrates its many distinct ligands and stimuli into context-specific SHP-1 versus SHP-2 outputs, and the precise enzymatic step linking phosphatase recruitment to integrin inside-out inhibition at the synapse, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model of stimulus-to-phosphatase selectivity\", \"Direct kinase responsible for cytoplasmic tyrosine phosphorylation in vivo unsettled\", \"Mechanistic chain from SHP recruitment to integrin regulation incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 8, 31]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 14, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 15, 18, 25]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9, 26]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 14, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 18, 25, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 14, 27]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [8, 9, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD47\", \"PTPN11\", \"PTPN6\", \"JAK2\", \"SHC1\", \"SFTPA1\", \"SFTPD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}