SIRPB1

SIRPB1 is a DAP12-coupled activating receptor on myeloid cells that transduces signals through SYK, MAPK, NF-κB, and calcium pathways to regulate inflammatory cytokine production and osteoclast differentiation. Association with DAP12 is required for efficient SIRPB1 surface expression, and antibody-mediated or gain-of-function stimulation of the SIRPB1–DAP12 complex induces SYK and Akt phosphorylation, leading to production of IL-1, TNF-α, IL-6, CCL2, and IL-8 in macrophages (PMID:10604985, PMID:38594692, PMID:37323681). In cancer contexts, SIRPB1 promotes proliferation, migration, and invasion through Akt activation in prostate cancer and through SOCS1 suppression and consequent STAT3 de-repression in melanoma (PMID:31905248, PMID:41467177). SIRPB1 expression is modulated by a common intron-1 copy-number variant that alters 3D chromatin contacts between the promoter and downstream enhancer/insulator elements (PMID:25039969, PMID:29518122, PMID:32998049).

1. 2000 High

   The fundamental signaling partnership of SIRPB1 was established: it requires DAP12 for surface expression and, upon ligation, triggers tyrosine phosphorylation and MAPK activation in monocytes and dendritic cells, resolving how this short-tailed receptor transduces activating signals.

   Evidence Co-immunoprecipitation and anti-SIRP mAb stimulation of monocytes and dendritic cells

   PMID:10604985

   Open questions at the time

   • The proximal kinase (SYK vs ZAP-70) downstream of DAP12 in the SIRPB1 complex was not identified
   • Natural ligand for SIRPB1 remains unknown
   • Functional consequences for cytokine output were not measured
2. 2014 Medium

   A common copy-number variant in SIRPB1 intron 1 was shown to function as a cis-regulatory element—containing insulator activity and acting as an eQTL—demonstrating that structural variation controls SIRPB1 expression levels and linking this to impulsive-disinhibited personality traits.

   Evidence Genome-wide CNV association, eQTL analysis, and zebrafish insulator reporter assay

   PMID:25039969

   Open questions at the time

   • Causal relationship between SIRPB1 expression and behavioral phenotype was not established by direct manipulation
   • Cell-type specificity of the eQTL (myeloid vs neuronal) was not resolved
3. 2018 Medium

   3D chromatin topology studies revealed that the intron-1 CNV reshapes promoter–enhancer contacts at the SIRPB1 locus, and a downstream enhancer drives neural expression, explaining how the structural variant mechanistically alters transcriptional output.

   Evidence 4C-seq from SIRPB1 promoter and transgenic enhancer reporter in zebrafish

   PMID:29518122 PMID:32998049

   Open questions at the time

   • Whether altered 3D contacts quantitatively change SIRPB1 protein levels in human tissues was not shown
   • Identity of transcription factors mediating enhancer activity was unknown at the time
4. 2020 High

   SIRPB1 was shown to function as an oncogenic driver in prostate cancer, promoting proliferation, migration, invasion, and xenograft growth through Akt phosphorylation, with Akt inhibition abolishing these effects—extending SIRPB1 signaling beyond immune cells to a cancer-intrinsic growth pathway.

   Evidence siRNA knockdown, overexpression, xenograft tumor model, pharmacological Akt inhibition in prostate cancer cell lines

   PMID:31905248

   Open questions at the time

   • Whether SIRPB1 signals through DAP12 in epithelial cancer cells was not addressed
   • The upstream trigger for SIRPB1 activation in the tumor microenvironment was not identified
5. 2023 Medium

   A rare gain-of-function frameshift variant in SIRPB1 was found to hyperactivate DAP12, SYK, Akt, JAK2, and NF-κB in macrophages, driving excessive IL-1, TNF-α, and IL-6 production—demonstrating that SIRPB1 variants can cause pathological inflammatory signaling in humans.

   Evidence Family-based WGS, replication cohort, functional macrophage assays for phosphorylation and cytokine output

   PMID:37323681

   Open questions at the time

   • The mechanism by which a frameshift increases receptor expression and signaling is unclear (stabilization vs. trafficking effect)
   • Not independently replicated in a second laboratory
   • Clinical phenotype associated with this variant was not fully characterized
6. 2024 High

   CRISPR knockout and rescue experiments definitively placed SYK as the essential proximal kinase downstream of SIRPB1, showing that SIRPB1 activation drives calcium, MAPK, and NF-κB signaling to regulate IL1RA, CCL2, and IL-8 in macrophages, a pathway fully blocked by the SYK inhibitor GS9973.

   Evidence CRISPR/Cas9 KO, ectopic re-expression, SYK inhibitor GS9973, cytokine profiling in macrophage–glioma co-culture

   PMID:38594692

   Open questions at the time

   • Natural ligand on glioma cells engaging SIRPB1 was not identified
   • Relative contribution of SIRPB1 vs other DAP12-paired receptors in tumor-associated macrophages is unresolved
7. 2025 Medium

   In melanoma, SIRPB1 was shown to promote tumorigenicity through a distinct mechanism—suppressing SOCS1 to de-repress STAT3—and USF2 was identified as a transcription factor driving SIRPB1 expression, adding a second cancer-relevant signaling axis beyond Akt.

   Evidence siRNA knockdown, overexpression, in vivo tumor model, STAT3 agonist rescue, USF2 promoter binding assay in melanoma cells

   PMID:41467177

   Open questions at the time

   • How SIRPB1 suppresses SOCS1 (transcriptional vs post-transcriptional) is not defined
   • Whether USF2-driven transcription operates in myeloid cells or is cancer-specific is unknown

• The natural ligand for SIRPB1 remains unidentified, and it is unknown whether immune and cancer signaling functions use the same or distinct proximal mechanisms (DAP12-dependent vs DAP12-independent).
• No natural ligand has been identified for SIRPB1
• Whether SIRPB1 signals independently of DAP12 in epithelial cancer cells has not been tested
• No structural model of the SIRPB1 extracellular domain–ligand interface exists