Affinage

Showing SIRPA — SHPS-1 is a alias.

SIRPA

Tyrosine-protein phosphatase non-receptor type substrate 1 · UniProt P78324

Length
504 aa
Mass
55.0 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    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

    PMID:8943344

    Open questions at the time
    • Did not identify the physiological ligand
    • Did not establish cell-type-specific phosphatase preference
  2. 1998 High

    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

    PMID:9507023 PMID:9535915 PMID:9582366 PMID:9662335 PMID:9712903

    Open questions at the time
    • 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
  3. 2000 High

    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

    PMID:10725722 PMID:10940903

    Open questions at the time
    • Low-micromolar affinity left the functional relevance of trans-interaction strength open
    • Did not resolve structural basis of binding
  4. 2000 High

    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

    PMID:11118207

    Open questions at the time
    • How SIRPA couples to Rho regulators mechanistically was not defined
    • Did not connect this to phagocytosis at the time
  5. 2002 High

    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

    PMID:12167615

    Open questions at the time
    • Did not pinpoint the inhibited phagocytic signaling node
    • Ligand dependence of the in vivo phenotype unresolved
  6. 2003 High

    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

    PMID:12773380 PMID:12972543

    Open questions at the time
    • How CD47 binding triggers dephosphorylation mechanistically not resolved
    • Phosphatase responsible for SIRPA dephosphorylation not identified
  7. 2005 High

    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

    PMID:15699129

    Open questions at the time
    • Did not establish how SHP-1 acts on Syk/PI3K substrates
    • Spatial organization of the inhibition was not addressed
  8. 2005 High

    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

    PMID:11779860 PMID:15888547

    Open questions at the time
    • Generalizability beyond IGF-I/smooth muscle context not established
    • Stoichiometry of the SHP-2 transfer reaction unknown
  9. 2008 High

    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

    PMID:18233962 PMID:18349073 PMID:18420961 PMID:18450421

    Open questions at the time
    • How a single scaffold discriminates among CD47, SP-A/SP-D and signaling outputs not resolved
    • In vivo significance of trans-endocytosis incompletely defined
  10. 2007 High

    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

    PMID:17982459 PMID:18025220 PMID:18045614 PMID:24269920

    Open questions at the time
    • Did not co-crystallize the SIRPA–CD47 complex in these entries
    • Functional consequence of dimer interface in vivo unresolved
  11. 2011 High

    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

    PMID:21638321

    Open questions at the time
    • Mechanistic link between SHP-1 and myosin IIA dephosphorylation not fully defined
    • Whether this requires phagocytic-synapse-like organization unknown
  12. 2020 High

    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

    PMID:32768386

    Open questions at the time
    • 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
  13. 2023 Medium

    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

    PMID:37769797

    Open questions at the time
    • Single-lab finding awaiting independent confirmation
    • How SIRPA activates ERK in this context not mechanistically connected to its known scaffold tyrosines

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CD47JAK2PTPN11PTPN6SFTPA1SFTPDSHC1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. cDNA cloning, co-immunoprecipitation, in vitro kinase assay, purification from v-src-transformed fibroblasts Molecular and cellular biology High 8943344
1998 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. Co-immunoprecipitation from macrophage cell lines and peritoneal macrophages, immunoblotting The Journal of biological chemistry Medium 9712903
1998 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. In vitro phosphorylation assay, overexpression of Csk, FAK-deficient cells, MAP kinase activation assays, co-immunoprecipitation The Journal of biological chemistry High 9582366
1998 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. Site-directed mutagenesis, surface plasmon resonance, in vitro phosphatase assay, MAP kinase activation assay in CHO cells overexpressing insulin receptor The Journal of biological chemistry High 9535915
1998 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. Co-immunoprecipitation, co-expression in COS cells, immunoblotting with phosphotyrosine antibodies The Journal of biological chemistry Medium 9507023
1998 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). Inhibitor treatments (C3 exoenzyme, pertussis toxin), FAK-null cells, Csk overexpression, co-immunoprecipitation Oncogene Medium 9662335
1999 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. Mass spectrometry identification, co-immunoprecipitation, immunoblotting in adherent macrophages Current biology : CB Medium 10469599
1999 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. Co-immunoprecipitation, immunoblotting, phosphatase activity assay Journal of neurochemistry Medium 10098842
2000 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). Affinity chromatography, peptide sequencing, surface plasmon resonance with purified recombinant proteins European journal of immunology High 10940903
2000 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. Cell aggregation assay, anti-CD47 antibody blocking, CD47-null erythrocyte rosetting, truncation mutants Journal of immunology Medium 10725722
2000 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. Fibroblast knock-in mutant mice (SHPS-1 cytoplasmic deletion), phalloidin staining, cell motility assay, Rho/Rac activity assays The EMBO journal High 11118207
2000 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. Recombinant adenovirus overexpression, PI3K inhibitor (LY294002), Akt phosphorylation immunoblotting, neuronal survival counting Journal of neurochemistry Medium 10987830
2002 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. SHPS-1 cytoplasmic-deletion knock-in mice, platelet clearance assay, ex vivo phagocytosis assay, morphological analysis The Journal of biological chemistry High 12167615
2002 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. GSE retroviral library screen, NF-κB reporter assay, Akt phosphorylation immunoblotting, wortmannin inhibition The Journal of biological chemistry Medium 12446684
2002 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. SHPS-1 SHP-2 binding mutant expression, co-immunoprecipitation, catalytically inactive SHP-2, IGF-IR phosphorylation time-course in smooth muscle cells The Journal of biological chemistry High 11779860
2003 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. CD47-Fc ligand, anti-SHPS-1 antibodies, SHPS-1 phosphorylation mutant (4F), migration assays, Rho activity assay The EMBO journal High 12773380
2003 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). IAP monoclonal antibody blocking, mutant IAP that does not bind SHPS-1, co-immunoprecipitation, cell proliferation assay, migration assay Molecular biology of the cell High 12972543
2004 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. 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 The Journal of biological chemistry High 15123722
2005 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). 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 of immunology High 15699129
2005 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. Cell-permeable inhibitory peptides (phospho-tyrosine binding motif, polyproline), SHPS-1 binding mutant, Shc proline-to-alanine mutant, co-immunoprecipitation, MAPK phosphorylation assays Molecular biology of the cell High 15888547
2006 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. In vivo RBC clearance assay (transfusion of CD47-null RBCs into SHPS-1 mutant mice), ex vivo phagocytosis assay Biochemical and biophysical research communications Medium 16580635
2007 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. Positional genetics/backcross mapping, binding assays with recombinant proteins, macrophage depletion, xenotransplantation engraftment assays Nature immunology High 17982459
2007 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. X-ray crystallography, site-directed mutagenesis, CD47-binding assays Journal of molecular biology High 18045614
2007 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. Site-directed mutagenesis, domain swapping between SIRPalpha and SIRPbeta, CD47-binding assays, homology modeling onto crystal structure, anti-SIRP antibody epitope mapping Journal of immunology High 18025220
2008 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. 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 American journal of respiratory and critical care medicine High 18420961
2008 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. SHPS-1 4F phosphorylation mutant expression, CD8-cytoplasmic chimeric construct, NF-κB reporter assay, co-immunoprecipitation, cytokine ELISA, Src inhibitor Genes to cells High 18233962
2008 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. 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 of cell science High 18349073
2008 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. SHPS-1 cytoplasmic deletion mutant MEFs, co-immunoprecipitation, ERK/STAT3 phosphorylation immunoblotting, STAT3 reporter gene assay Cellular signalling Medium 18450421
2011 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. 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 of bone and mineral research High 21638321
2012 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. 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 of neurochemistry Medium 22671569
2013 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. Binding assays with strain-specific SIRPA proteins, in vitro phagocytosis assay against human HSCs, xenotransplantation engraftment, single nucleotide polymorphism analysis Experimental hematology Medium 24269920
2020 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. Reconstituted phagocytic synapse system with defined signals, live-cell imaging of SIRPA localization, integrin activation assays, chemical integrin agonist bypass experiment Immunity High 32768386
2017 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. Live-cell imaging of CD47-Treg/SIRPA-neuron contact, siRNA knockdown, transwell co-culture controls, Rac1/Akt inhibitors, TH-immunoreactive cell counting Cellular physiology and biochemistry Medium 28268219
2023 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. 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 Cancer letters Medium 37769797

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Sciences of the United States of America 1371 22451913
2011 Notch signalling in solid tumours: a little bit of everything but not all the time. Nature reviews. Cancer 677 21508972
2011 SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nature biotechnology 404 22020386
2007 Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nature immunology 404 17982459
1996 A novel membrane glycoprotein, SHPS-1, that binds the SH2-domain-containing protein tyrosine phosphatase SHP-2 in response to mitogens and cell adhesion. Molecular and cellular biology 386 8943344
2006 The SIRP family of receptors and immune regulation. Nature reviews. Immunology 342 16691243
2005 Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system. Journal of immunology (Baltimore, Md. : 1950) 251 15699129
1998 High expression of inhibitory receptor SHPS-1 and its association with protein-tyrosine phosphatase SHP-1 in macrophages. The Journal of biological chemistry 201 9712903
2000 Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Current opinion in oncology 199 11085453
2020 CD47 Ligation Repositions the Inhibitory Receptor SIRPA to Suppress Integrin Activation and Phagocytosis. Immunity 182 32768386
2008 Surfactant proteins A and D suppress alveolar macrophage phagocytosis via interaction with SIRP alpha. American journal of respiratory and critical care medicine 173 18420961
2011 Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proceedings of the National Academy of Sciences of the United States of America 160 21788504
2000 CD47 is a ligand for rat macrophage membrane signal regulatory protein SIRP (OX41) and human SIRPalpha 1. European journal of immunology 151 10940903
2004 Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family. Journal of immunology (Baltimore, Md. : 1950) 131 15294972
1998 Integrin-mediated tyrosine phosphorylation of SHPS-1 and its association with SHP-2. Roles of Fak and Src family kinases. The Journal of biological chemistry 126 9582366
2013 Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. Blood 118 23293079
2015 Dihydroceramides: From Bit Players to Lead Actors. The Journal of biological chemistry 116 25947377
2000 SHPS-1 regulates integrin-mediated cytoskeletal reorganization and cell motility. The EMBO journal 116 11118207
2002 Negative regulation of platelet clearance and of the macrophage phagocytic response by the transmembrane glycoprotein SHPS-1. The Journal of biological chemistry 110 12167615
1998 Cloning of two members of the SIRP alpha family of protein tyrosine phosphatase binding proteins in cattle that are expressed on monocytes and a subpopulation of dendritic cells and which mediate binding to CD4 T cells. European journal of immunology 108 9485180
2021 BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy. Aging cell 107 33656257
1998 Roles of the complex formation of SHPS-1 with SHP-2 in insulin-stimulated mitogen-activated protein kinase activation. The Journal of biological chemistry 105 9535915
2017 SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors. Current biology : CB 93 28669759
2002 SHPS-1, a multifunctional transmembrane glycoprotein. FEBS letters 87 12023008
2000 Inducible nitric oxide synthase: a little bit of good in all of us. Gut 87 10861252
2019 Engineering macrophages to phagocytose cancer cells by blocking the CD47/SIRPɑ axis. Cancer medicine 83 31183992
2020 Intracellular Entropy-Driven Multi-Bit DNA Computing for Tumor Progression Discrimination. Angewandte Chemie (International ed. in English) 81 32367682
1999 SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages. Current biology : CB 80 10469599
1998 Growth hormone regulation of SIRP and SHP-2 tyrosyl phosphorylation and association. The Journal of biological chemistry 80 9507023
2002 Regulation of insulin-like growth factor I receptor dephosphorylation by SHPS-1 and the tyrosine phosphatase SHP-2. The Journal of biological chemistry 79 11779860
2019 RRx-001 Acts as a Dual Small Molecule Checkpoint Inhibitor by Downregulating CD47 on Cancer Cells and SIRP-α on Monocytes/Macrophages. Translational oncology 78 30738349
2009 Selective control of SIRP-alpha-positive airway dendritic cell trafficking through CD47 is critical for the development of T(H)2-mediated allergic inflammation. The Journal of allergy and clinical immunology 76 19748659
2020 Just eat it: A review of CD47 and SIRP-α antagonism. Seminars in oncology 74 32517874
1997 The murine P84 neural adhesion molecule is SHPS-1, a member of the phosphatase-binding protein family. The Journal of neuroscience : the official journal of the Society for Neuroscience 73 9348339
2003 Role of the CD47-SHPS-1 system in regulation of cell migration. The EMBO journal 70 12773380
1997 BIT, an immune antigen receptor-like molecule in the brain. FEBS letters 70 9271230
2003 A bit of give and take: the relationship between the extracellular matrix and the developing chondrocyte. Mechanisms of development 69 14623441
2008 CD47 in the immune response: role of thrombospondin and SIRP-alpha reverse signaling. Current drug targets 67 18855618
2017 Replication Study: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. eLife 58 28100392
2015 SIRP/CD47 signaling in neurological disorders. Brain research 58 25795378
2000 Expression of a synapse-associated membrane protein, P84/SHPS-1, and its ligand, IAP/CD47, in mouse retina. The Journal of comparative neurology 58 10602092
2010 Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research 56 20705613
2014 SIRPA, VCAM1 and CD34 identify discrete lineages during early human cardiovascular development. Stem cell research 54 24968096
2005 Role of SHPS-1 in the regulation of insulin-like growth factor I-stimulated Shc and mitogen-activated protein kinase activation in vascular smooth muscle cells. Molecular biology of the cell 54 15888547
2003 A novel MyD-1 (SIRP-1alpha) signaling pathway that inhibits LPS-induced TNFalpha production by monocytes. Blood 51 12805067
2013 Split intein mediated ultra-rapid purification of tagless protein (SIRP). Biotechnology and bioengineering 45 23568256
2003 The association between integrin-associated protein and SHPS-1 regulates insulin-like growth factor-I receptor signaling in vascular smooth muscle cells. Molecular biology of the cell 45 12972543
1997 Mouse and human SHPS-1: molecular cloning of cDNAs and chromosomal localization of genes. Biochemical and biophysical research communications 45 9070220
2019 Come a little bit closer! Lipid droplet-ER contact sites are getting crowded. Biochimica et biophysica acta. Molecular cell research 44 31733263
2006 Influence of spatial resolution and bit depth on detection of small caries lesions with digital receptors. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 44 17321456
2000 SHPS-1 induces aggregation of Ba/F3 pro-B cells via an interaction with CD47. Journal of immunology (Baltimore, Md. : 1950) 42 10725722
2011 Bit-1 mediates integrin-dependent cell survival through activation of the NFkappaB pathway. The Journal of biological chemistry 41 21383007
2017 Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 40 28268219
2004 Enrichment for a CD26hi SIRP- subset in lymph dendritic cells from the upper aero-digestive tract. Journal of leukocyte biology 40 15197234
2022 Tumor-intrinsic SIRPA promotes sensitivity to checkpoint inhibition immunotherapy in melanoma. Cancer cell 39 36332624
2013 The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment. Experimental hematology 39 24269920
2012 SHPS-1 deficiency induces robust neuroprotection against experimental stroke by attenuating oxidative stress. Journal of neurochemistry 38 22671569
2025 A RISC-V 32-bit microprocessor based on two-dimensional semiconductors. Nature 37 40175546
1999 Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins. Journal of neurochemistry 37 10098842
2011 An essential role for the association of CD47 to SHPS-1 in skeletal remodeling. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 36 21638321
2006 The chicken immunoregulatory receptor families SIRP, TREM, and CMRF35/CD300L. Immunogenetics 36 16493555
2004 Ectodomain shedding of SHPS-1 and its role in regulation of cell migration. The Journal of biological chemistry 35 15123722
1997 Epidermal growth factor stimulates the tyrosine phosphorylation of SHPS-1 and association of SHPS-1 with SHP-2, a SH2 domain-containing protein tyrosine phosphatase. Biochemical and biophysical research communications 35 9344856
2022 Scaling Up Multi-bit DNA Full Adder Circuits with Minimal Strand Displacement Reactions. Journal of the American Chemical Society 34 35603742
1997 Nested genetic bit analysis (N-GBA) for mutation detection in the p53 tumor suppressor gene. Nucleic acids research 34 9396817
1999 Gene structure of mouse BIT/SHPS-1. The Biochemical journal 33 10585853
2023 SIRPA enhances osteosarcoma metastasis by stabilizing SP1 and promoting SLC7A3-mediated arginine uptake. Cancer letters 32 37769797
2006 Enhanced phagocytosis of CD47-deficient red blood cells by splenic macrophages requires SHPS-1. Biochemical and biophysical research communications 32 16580635
2002 Dominant negative form of signal-regulatory protein-alpha (SIRPalpha /SHPS-1) inhibits tumor necrosis factor-mediated apoptosis by activation of NF-kappa B. The Journal of biological chemistry 30 12446684
2010 SIRP-alpha-CD47 system functions as an intercellular signal in the renal glomerulus. American journal of physiology. Renal physiology 29 20554646
2000 SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. Recent progress in hormone research 29 11036942
2023 Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition. NPJ precision oncology 28 37468567
2022 4-bit adhesion logic enables universal multicellular interface patterning. Nature 28 35948712
2016 Comparative Analysis of piggyBac, CRISPR/Cas9 and TALEN Mediated BAC Transgenesis in the Zygote for the Generation of Humanized SIRPA Rats. Scientific reports 28 27530248
2008 Trans-endocytosis of CD47 and SHPS-1 and its role in regulation of the CD47-SHPS-1 system. Journal of cell science 28 18349073
2000 BIT/SHPS-1 enhances brain-derived neurotrophic factor-promoted neuronal survival in cultured cerebral cortical neurons. Journal of neurochemistry 28 10987830
1994 6-bit and 8-bit digital radiography for detecting simulated periodontal lesions. Oral surgery, oral medicine, and oral pathology 28 8015807
2021 Treating lymphoma is now a bit EZ-er. Blood advances 27 33904892
2016 "Marker of Self" CD47 on lentiviral vectors decreases macrophage-mediated clearance and increases delivery to SIRPA-expressing lung carcinoma tumors. Molecular therapy. Methods & clinical development 27 28053997
2011 A biclustering algorithm for extracting bit-patterns from binary datasets. Bioinformatics (Oxford, England) 27 21824973
2007 Novel structural determinants on SIRP alpha that mediate binding to CD47. Journal of immunology (Baltimore, Md. : 1950) 27 18025220
2018 DNA multi-bit non-volatile memory and bit-shifting operations using addressable electrode arrays and electric field-induced hybridization. Nature communications 26 29348493
2019 Eutopic endometrium from patients with endometriosis modulates the expression of CD36 and SIRP-α in peritoneal macrophages. The journal of obstetrics and gynaecology research 25 30843336
2000 v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells. Oncogene 24 10763828
2008 SHPS-1/SIRP1alpha contributes to interleukin-6 signalling. Cellular signalling 23 18450421
2008 Resistance to collagen-induced arthritis in SHPS-1 mutant mice. Biochemical and biophysical research communications 23 18455510
1998 Lysophosphatidic acid-induced association of SHP-2 with SHPS-1: roles of RHO, FAK, and a SRC family kinase. Oncogene 23 9662335
2022 MicroRNA-382 Promotes M2-Like Macrophage via the SIRP-α/STAT3 Signaling Pathway in Aristolochic Acid-Induced Renal Fibrosis. Frontiers in immunology 21 35585990
2020 A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells. Blood 21 32206775
2004 Resistance of B16 melanoma cells to CD47-induced negative regulation of motility as a result of aberrant N-glycosylation of SHPS-1. The Journal of biological chemistry 21 14739297
2022 Lack of SIRP-alpha reduces lung cancer growth in mice by promoting anti-tumour ability of macrophages and neutrophils. Cell proliferation 20 36419386
2021 Comparative study of two isothiazolinone biocides, 1,2-benzisothiazolin-3-one (BIT) and 4,5-dichloro-2-n-octyl-isothiazolin-3-one (DCOIT), on barrier function and mitochondrial bioenergetics using murine brain endothelial cell line (bEND.3). Journal of toxicology and environmental health. Part A 20 34315345
2018 Making glycoproteins a little bit sweeter with PDB-REDO. Acta crystallographica. Section F, Structural biology communications 20 30084395
2009 Identification of novel SHPS-1-associated proteins and their roles in regulation of insulin-like growth factor-dependent responses in vascular smooth muscle cells. Molecular & cellular proteomics : MCP 20 19299420
2019 A little bit of sex prevents mutation accumulation even in apomictic polyploid plants. BMC evolutionary biology 19 31412772
2015 Bit-1 is an essential regulator of myogenic differentiation. Journal of cell science 18 25770104
2008 Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages. Genes to cells : devoted to molecular & cellular mechanisms 18 18233962
2007 Structural insight into the specific interaction between murine SHPS-1/SIRP alpha and its ligand CD47. Journal of molecular biology 18 18045614
2002 A role for SHPS-1/SIRPalpha1 in IL-1beta- and TNFalpha-dependent signaling. Oncogene 18 12483539
2000 Molecular cloning of a novel human gene (SIRP-B2) which encodes a new member of the SIRP/SHPS-1 protein family. Journal of human genetics 18 11185750

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