SIRPB1

SIRPB1 is an activating immunoreceptor of the signal-regulatory protein family expressed on myeloid cells that lacks cytoplasmic ITIM motifs and instead transduces signals by associating with the adaptor DAP12, with which it must complex for efficient cell-surface expression (PMID:10604985). Receptor engagement triggers tyrosine phosphorylation and SYK activation, driving downstream calcium, MAPK, and NF-κB signaling and the production of pro-inflammatory cytokines, as shown by CRISPR knockout, ectopic re-expression, and SYK-inhibitor rescue in myeloid cells where SIRPB1 controls IL-1RA, CCL2, and IL-8 output (PMID:10604985, PMID:38594692). A rare gain-of-function frameshift variant amplifies this axis, elevating SIRPB1 expression and inducing phosphorylation of Syk, Akt, and Jak2 with DAP12 and NF-κB activation and IL-1/TNF-α/IL-6 synthesis (PMID:37323681). Beyond its myeloid signaling role, SIRPB1 promotes tumorigenicity: it drives prostate cancer proliferation and invasion through Akt activation (PMID:31905248) and melanoma growth through the SOCS1/STAT3 axis (PMID:41467177), where its transcription is controlled by USF2 binding the SIRPB1 promoter (PMID:41467177). At the locus level, a common intronic copy-number variant carries functional insulator elements and enhancer activity that modulate SIRPB1 expression and 3D chromatin architecture (PMID:29518122, PMID:25039969).

1. 2000 High

   Established how an ITIM-lacking SIRP family member signals: SIRPB1 partners with DAP12 to become an activating rather than inhibitory receptor, resolving how it couples to downstream activation.

   Evidence SIRP-specific mAb co-immunoprecipitation, surface-expression assays, and phosphorylation/MAPK readouts in monocytes and dendritic cells

   PMID:10604985

   Open questions at the time

   • Endogenous ligand of SIRPB1 not identified
   • Stoichiometry and structural basis of the SIRPB1/DAP12 complex not resolved
2. 2013 Low

   Placed SIRPB1 within DAP12-dependent myeloid autoimmune responses in vivo, though only by inference from DAP12 loss rather than direct manipulation of SIRPB1.

   Evidence qRT-PCR of DAP12/SIRPb1 in mouse eye, DAP12 knockout mice, experimental autoimmune uveitis

   PMID:23906311

   Open questions at the time

   • No SIRPB1-specific gain/loss-of-function; role inferred from DAP12 context
   • Effect direction confounded by microbial environment
3. 2014 Medium

   Identified a cis-regulatory mechanism controlling SIRPB1 dosage: an intronic CNV bearing insulator elements sets steady-state SIRPB1 mRNA levels.

   Evidence Genome-wide CNV and eQTL analysis with functional insulator assays in zebrafish embryos

   PMID:25039969

   Open questions at the time

   • Insulator-binding factors not identified
   • Cell-type specificity of the regulatory effect unresolved
4. 2018 Medium

   Extended the regulatory model to 3D chromatin architecture, showing the intronic CNV reshapes locus topology and that a 3' enhancer has neural activity.

   Evidence 4C-seq from SIRPB1 promoter, transgenic zebrafish enhancer assay, population CNV analysis

   PMID:29518122

   Open questions at the time

   • Functional consequence on CNS SIRPB1 expression not directly measured in humans
   • Link between chromatin change and phenotype unestablished
5. 2020 High

   Revealed an oncogenic function distinct from immune signaling: SIRPB1 drives prostate cancer proliferation and invasion via Akt.

   Evidence siRNA knockdown, overexpression, colony/migration assays, xenografts, and Akt-inhibitor rescue in PC3 and C4-2 cells

   PMID:31905248

   Open questions at the time

   • Mechanism linking SIRPB1 to Akt activation not defined
   • Whether DAP12/SYK are required for the cancer-cell effect unknown
6. 2023 Medium

   Provided human genetic and functional evidence that elevated SIRPB1 activity is pathogenic, via a gain-of-function frameshift variant amplifying Syk/Akt/Jak2 and NF-κB-driven cytokine output.

   Evidence Family-based whole-genome sequencing with replication cohort and macrophage phosphorylation/NF-κB/cytokine assays

   PMID:37323681

   Open questions at the time

   • Functional findings from a single lab, not independently replicated
   • Specific disease causality of the variant not firmly established
7. 2024 High

   Defined SYK as the proximal kinase relaying SIRPB1 signaling to calcium, MAPK, and NF-κB and to specific inflammatory cytokines in a tumor-microenvironment context.

   Evidence CRISPR/Cas9 KO and ectopic re-expression in THP-1, SYK inhibitor (GS9973), macrophage-glioma co-culture, cytokine and phosphorylation assays

   PMID:38594692

   Open questions at the time

   • Trigger of SIRPB1 activation in the co-culture not identified
   • Contribution to glioma progression in vivo not tested
8. 2025 Medium

   Linked SIRPB1 to a second tumor-promoting axis (SOCS1/STAT3) and identified USF2 as its transcriptional activator, connecting expression control to oncogenic output.

   Evidence Knockdown/overexpression in melanoma cells, xenografts, STAT3-agonist rescue, dual-luciferase and ChIP for USF2

   PMID:41467177

   Open questions at the time

   • How SIRPB1 modulates SOCS1 mechanistically unknown
   • Single-lab findings not independently replicated

• The physiological extracellular ligand of SIRPB1 and how its myeloid DAP12/SYK signaling is reconciled with its cell-intrinsic oncogenic Akt and SOCS1/STAT3 functions remain unresolved.
• No endogenous ligand identified
• No structural model of receptor/adaptor complex
• Unclear whether cancer-cell and myeloid signaling use the same DAP12/SYK module