Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0007155 cell adhesion	IBA GO_REF:0000033	MODIFY	Summary: CD33 mediates sialic-acid-dependent cell-cell interactions, but the broad cell adhesion term should be replaced with the more specific cell-cell adhesion term already supported for CD33. Reason: The sialoadhesin/Siglec evidence supports sialic-acid-dependent cell-cell adhesion rather than a broad adhesion process. Proposed replacements: cell-cell adhesion
GO:0033691 sialic acid binding	IBA GO_REF:0000033	ACCEPT	Summary: Sialic acid binding is the defining extracellular Siglec molecular function of CD33. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0005777 peroxisome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Peroxisome localization is supported for the CD33m splice isoform that lacks the sialic-acid-binding domain and is diverted away from the cell surface, especially in Alzheimer disease genetics context. Reason: Retain as non-core because the annotation is supported or plausible but reflects isoform-specific intracellular localization, receptor biosynthesis/trafficking, or neutrophil granule context rather than the main cell-surface inhibitory Siglec role.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0005515 protein binding	IPI PMID:10206955 The myeloid-specific sialic acid-binding receptor, CD33, ass...	MARK AS OVER ANNOTATED	Summary: These studies support SHP-1/SHP-2 interaction, which is better captured by the specific protein phosphatase binding annotation. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0005515 protein binding	IPI PMID:10556798 The sialoadhesin CD33 is a myeloid-specific inhibitory recep...	MARK AS OVER ANNOTATED	Summary: These studies support SHP-1/SHP-2 interaction, which is better captured by the specific protein phosphatase binding annotation. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0005515 protein binding	IPI PMID:17947393 ITIM-dependent endocytosis of CD33-related Siglecs: role of ...	MARK AS OVER ANNOTATED	Summary: This protein interaction annotation is too generic or high-throughput to clarify CD33 molecular function. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0005515 protein binding	IPI PMID:24216507 Induction of myelodysplasia by myeloid-derived suppressor ce...	MARK AS OVER ANNOTATED	Summary: This protein interaction annotation is too generic or high-throughput to clarify CD33 molecular function. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This protein interaction annotation is too generic or high-throughput to clarify CD33 molecular function. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This protein interaction annotation is too generic or high-throughput to clarify CD33 molecular function. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0005515 protein binding	IPI PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw...	MARK AS OVER ANNOTATED	Summary: This protein interaction annotation is too generic or high-throughput to clarify CD33 molecular function. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0005886 plasma membrane	IDA GO_REF:0000052	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0005777 peroxisome	EXP PMID:28747436 The Alzheimer's disease-protective CD33 splice variant media...	KEEP AS NON CORE	Summary: Peroxisome localization is supported for the CD33m splice isoform that lacks the sialic-acid-binding domain and is diverted away from the cell surface, especially in Alzheimer disease genetics context. Reason: Retain as non-core because the annotation is supported or plausible but reflects isoform-specific intracellular localization, receptor biosynthesis/trafficking, or neutrophil granule context rather than the main cell-surface inhibitory Siglec role.
GO:0005886 plasma membrane	EXP PMID:10611343 Engagement of p75/AIRM1 or CD33 inhibits the proliferation o...	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0005886 plasma membrane	EXP PMID:28747436 The Alzheimer's disease-protective CD33 splice variant media...	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0008160 protein tyrosine phosphatase activator activity	IMP PMID:10556798 The sialoadhesin CD33 is a myeloid-specific inhibitory recep...	ACCEPT	Summary: Phosphorylated CD33 ITIM motifs recruit and activate SHP-1/SHP-2 protein tyrosine phosphatases, forming the core inhibitory signaling mechanism. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0019903 protein phosphatase binding	IPI PMID:10556798 The sialoadhesin CD33 is a myeloid-specific inhibitory recep...	ACCEPT	Summary: Phosphorylated CD33 ITIM motifs recruit and activate SHP-1/SHP-2 protein tyrosine phosphatases, forming the core inhibitory signaling mechanism. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0038094 Fc-gamma receptor signaling pathway	IDA PMID:10556798 The sialoadhesin CD33 is a myeloid-specific inhibitory recep...	ACCEPT	Summary: CD33 ITIM/SHP signaling down-regulates Fc-gamma receptor-induced calcium signaling, so this pathway context is consistent with the inhibitory receptor role. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0005794 Golgi apparatus	IDA PMID:21278227 Epitope mapping, expression and post-translational modificat...	KEEP AS NON CORE	Summary: This intracellular or granule-membrane localization is compatible with CD33 biosynthesis, trafficking, or myeloid granule context, but it is not the main functional site of full-length CD33M inhibitory signaling. Reason: Retain as non-core because the annotation is supported or plausible but reflects isoform-specific intracellular localization, receptor biosynthesis/trafficking, or neutrophil granule context rather than the main cell-surface inhibitory Siglec role.
GO:0005886 plasma membrane	IDA PMID:21278227 Epitope mapping, expression and post-translational modificat...	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0150102 negative regulation of monocyte activation	IDA PMID:15597323 Constitutive repressor activity of CD33 on human monocytes r...	ACCEPT	Summary: This immune-inhibitory/monocyte-cytokine regulation annotation reflects the core CD33 function in restraining myeloid cell activation. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0032691 negative regulation of interleukin-1 beta production	IMP PMID:15597323 Constitutive repressor activity of CD33 on human monocytes r...	ACCEPT	Summary: This immune-inhibitory/monocyte-cytokine regulation annotation reflects the core CD33 function in restraining myeloid cell activation. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0032717 negative regulation of interleukin-8 production	IMP PMID:15597323 Constitutive repressor activity of CD33 on human monocytes r...	ACCEPT	Summary: This immune-inhibitory/monocyte-cytokine regulation annotation reflects the core CD33 function in restraining myeloid cell activation. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0032720 negative regulation of tumor necrosis factor production	IMP PMID:15597323 Constitutive repressor activity of CD33 on human monocytes r...	ACCEPT	Summary: This immune-inhibitory/monocyte-cytokine regulation annotation reflects the core CD33 function in restraining myeloid cell activation. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0033691 sialic acid binding	IMP PMID:15597323 Constitutive repressor activity of CD33 on human monocytes r...	ACCEPT	Summary: Sialic acid binding is the defining extracellular Siglec molecular function of CD33. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0098609 cell-cell adhesion	IMP PMID:10206955 The myeloid-specific sialic acid-binding receptor, CD33, ass...	ACCEPT	Summary: CD33 can mediate sialic-acid-dependent cell-cell adhesion/interactions when expressed at the plasma membrane. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0033691 sialic acid binding	IMP PMID:7718872 Characterization of CD33 as a new member of the sialoadhesin...	ACCEPT	Summary: Sialic acid binding is the defining extracellular Siglec molecular function of CD33. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0098609 cell-cell adhesion	IMP PMID:7718872 Characterization of CD33 as a new member of the sialoadhesin...	ACCEPT	Summary: CD33 can mediate sialic-acid-dependent cell-cell adhesion/interactions when expressed at the plasma membrane. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0050714 positive regulation of protein secretion	IMP PMID:27044754 FRMD4A-cytohesin signaling modulates the cellular release of...	UNDECIDED	Summary: The cached abstract for the tau-release screen names FRMD4A as the functional hit and does not expose the CD33-specific data behind this IMP annotation. Reason: Use UNDECIDED because the supporting publication is abstract-only in the cache and the accessible abstract does not verify the CD33-specific protein secretion result.
GO:0002765 immune response-inhibiting signal transduction	IDA PMID:10887109 Myeloid specific human CD33 is an inhibitory receptor with d...	ACCEPT	Summary: This immune-inhibitory/monocyte-cytokine regulation annotation reflects the core CD33 function in restraining myeloid cell activation. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0005515 protein binding	IPI PMID:28325905 Evidence for C1q-mediated crosslinking of CD33/LAIR-1 inhibi...	MARK AS OVER ANNOTATED	Summary: C1q-CD33 interaction evidence is meaningful, but the generic protein binding term loses the specific inhibitory-receptor/C1q context. Reason: Generic protein binding is not informative for CD33 when the evidence supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
GO:0019903 protein phosphatase binding	IPI PMID:10887109 Myeloid specific human CD33 is an inhibitory receptor with d...	ACCEPT	Summary: Phosphorylated CD33 ITIM motifs recruit and activate SHP-1/SHP-2 protein tyrosine phosphatases, forming the core inhibitory signaling mechanism. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0035579 specific granule membrane	TAS Reactome:R-HSA-6799350	KEEP AS NON CORE	Summary: This intracellular or granule-membrane localization is compatible with CD33 biosynthesis, trafficking, or myeloid granule context, but it is not the main functional site of full-length CD33M inhibitory signaling. Reason: Retain as non-core because the annotation is supported or plausible but reflects isoform-specific intracellular localization, receptor biosynthesis/trafficking, or neutrophil granule context rather than the main cell-surface inhibitory Siglec role.
GO:0070821 tertiary granule membrane	TAS Reactome:R-HSA-6798747	KEEP AS NON CORE	Summary: This intracellular or granule-membrane localization is compatible with CD33 biosynthesis, trafficking, or myeloid granule context, but it is not the main functional site of full-length CD33M inhibitory signaling. Reason: Retain as non-core because the annotation is supported or plausible but reflects isoform-specific intracellular localization, receptor biosynthesis/trafficking, or neutrophil granule context rather than the main cell-surface inhibitory Siglec role.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-5685607	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798747	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6799350	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0009897 external side of plasma membrane	IDA PMID:20660734 MicroRNAs enriched in hematopoietic stem cells differentiall...	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0007155 cell adhesion	NAS PMID:10611343 Engagement of p75/AIRM1 or CD33 inhibits the proliferation o...	MODIFY	Summary: CD33 mediates sialic-acid-dependent cell-cell interactions, but the broad cell adhesion term should be replaced with the more specific cell-cell adhesion term already supported for CD33. Reason: The sialoadhesin/Siglec evidence supports sialic-acid-dependent cell-cell adhesion rather than a broad adhesion process. Proposed replacements: cell-cell adhesion
GO:0005886 plasma membrane	TAS PMID:3139766 Isolation of a cDNA encoding CD33, a differentiation antigen...	ACCEPT	Summary: Full-length CD33M is a type I plasma membrane/external cell-surface receptor on myeloid cells. Reason: This location is consistent with full-length CD33M acting as a type I cell-surface Siglec/inhibitory receptor on myeloid cells.
GO:0007165 signal transduction	TAS PMID:10611343 Engagement of p75/AIRM1 or CD33 inhibits the proliferation o...	ACCEPT	Summary: This broad signaling or proliferation annotation is supported by CD33 engagement experiments and fits the myeloid inhibitory receptor role. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0007267 cell-cell signaling	TAS PMID:10611343 Engagement of p75/AIRM1 or CD33 inhibits the proliferation o...	ACCEPT	Summary: This broad signaling or proliferation annotation is supported by CD33 engagement experiments and fits the myeloid inhibitory receptor role. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0008285 negative regulation of cell population proliferation	TAS PMID:10611343 Engagement of p75/AIRM1 or CD33 inhibits the proliferation o...	ACCEPT	Summary: This broad signaling or proliferation annotation is supported by CD33 engagement experiments and fits the myeloid inhibitory receptor role. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.
GO:0038023 signaling receptor activity	TAS PMID:10611343 Engagement of p75/AIRM1 or CD33 inhibits the proliferation o...	ACCEPT	Summary: This broad signaling or proliferation annotation is supported by CD33 engagement experiments and fits the myeloid inhibitory receptor role. Reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs and SHP-1/SHP-2 phosphatase recruitment.

Core Functions

CD33 is a Siglec whose extracellular Ig-like domain recognizes sialylated glycans, supporting sialic-acid-dependent cell-cell interactions and ligand-dependent control of myeloid inhibitory receptor activity.

Molecular Function:

sialic acid binding

Directly Involved In:

cell-cell adhesion immune response-inhibiting signal transduction negative regulation of monocyte activation

Cellular Locations:

external side of plasma membrane plasma membrane

Supporting Evidence:

PMID:7718872
CD33 can function as a sialic acid-dependent cell adhesion molecule
PMID:15597323
depending on the sialic acid microenvironment for its repressor activity
file:human/CD33/CD33-deep-research-falcon.md
CD33 functions as a lectin receptor that recognizes terminal sialic acids on cell-surface glycans rather than catalyzing enzymatic reactions

Upon receptor engagement, CD33 cytoplasmic ITIM tyrosines are phosphorylated and recruit SHP-1/PTPN6 and SHP-2/PTPN11 phosphatases, enabling inhibitory signaling that restrains myeloid activation, cytokine production, Fc-gamma receptor calcium responses, and proliferation.

Molecular Function:

protein phosphatase binding

Directly Involved In:

immune response-inhibiting signal transduction Fc-gamma receptor signaling pathway negative regulation of monocyte activation negative regulation of interleukin-1 beta production negative regulation of interleukin-8 production negative regulation of tumor necrosis factor production

Cellular Locations:

plasma membrane

Supporting Evidence:

PMID:10206955
Phosphorylated CD33 recruited both the protein-tyrosine phosphatases, SHP-1 and SHP-2
PMID:10887109
CD33 is an inhibitory receptor and also that SHP-1 phosphatase has a significant role in mediating CD33 function
PMID:10556798
CD33 is an inhibitory receptor that may regulate FcgammaRI signal transduction

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:10206955

The myeloid-specific sialic acid-binding receptor, CD33, associates with the protein-tyrosine phosphatases, SHP-1 and SHP-2.

PMID:10556798

The sialoadhesin CD33 is a myeloid-specific inhibitory receptor.

PMID:10611343

Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells.

PMID:10887109

Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2.

PMID:15597323

Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling.

PMID:17947393

ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2.

PMID:20660734

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output.

PMID:21278227

Epitope mapping, expression and post-translational modifications of two isoforms of CD33 (CD33M and CD33m) on lymphoid and myeloid human cells.

PMID:24216507

Induction of myelodysplasia by myeloid-derived suppressor cells.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:27044754

FRMD4A-cytohesin signaling modulates the cellular release of tau.

PMID:28325905

Evidence for C1q-mediated crosslinking of CD33/LAIR-1 inhibitory immunoreceptors and biological control of CD33/LAIR-1 expression.

PMID:28747436

The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool.

PMID:3139766

Isolation of a cDNA encoding CD33, a differentiation antigen of myeloid progenitor cells.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32822567

A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.

PMID:7718872

Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules.

Reactome:R-HSA-5685607

Sialic acid binds SIGLEC

Reactome:R-HSA-6798747

Exocytosis of tertiary granule membrane proteins

Reactome:R-HSA-6799350

Exocytosis of specific granule membrane proteins

file:human/CD33/CD33-deep-research-falcon.md

Falcon deep research report for CD33

Falcon corroborates the core CD33 model, framing it as a non-enzymatic sialic-acid-recognizing lectin receptor and adding microglial detail that CD33 inhibitory signaling antagonizes the SYK/ERK activation axis.

"In microglia, deletion or functional disruption of CD33 leads to increased phosphorylation of spleen tyrosine kinase (SYK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), indicating relief from CD33-mediated inhibition"

Suggested Experiments

Experiment: Compare full-length CD33M, CD33m, ITIM tyrosine mutants, and sialic-acid-binding mutants in primary human monocytes and iPSC-derived microglia for surface localization, SHP-1/SHP-2 recruitment, cytokine output, phagocytosis, and amyloid-beta uptake.

Hypothesis: CD33M suppresses myeloid/microglial activation through coupled sialic-acid recognition and ITIM/SHP signaling, whereas CD33m reduces this pathway primarily by cell-surface loss of function.

Type: isoform and ITIM separation-of-function assay

Experiment: Test C1q binding to CD33M and CD33m with purified ectodomains and monocyte/microglia surface assays, then measure whether C1q-dependent CD33/LAIR-1 crosslinking changes ITIM phosphorylation and inflammatory responses.

Hypothesis: C1q acts as a context-specific ligand/crosslinker for CD33 inhibitory signaling rather than a generic protein-binding partner.

Type: ligand-binding and inhibitory signaling assay

Deep Research

Falcon

(CD33-deep-research-falcon.md)

Comprehensive Research Report: CD33 (SIGLEC3) - Functional Annotation Falcon Edison Scientific Literature 19 citations 1 artifacts 2026-06-21T07:30:04.356007

Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: CD33 (SIGLEC3) - Functional Annotation

Gene Identity Verification

CD33 (UniProt P20138) is confirmed as Siglec-3 (sialic acid-binding immunoglobulin-like lectin 3), a myeloid cell surface antigen and member of the immunoglobulin superfamily in Homo sapiens (vu2025structureofthe pages 1-3, laubli2022targetingthesiglec–sialic pages 1-1). The protein is also known as gp67 and belongs to the CD33-related Siglec family, which has evolved rapidly through gene duplication and exon shuffling (laubli2022targetingthesiglec–sialic pages 2-3). This identity matches the UniProt description, confirming we are researching the correct human gene.

Protein Structure and Domain Organization

Overall Architecture

CD33 is a type I single-pass transmembrane receptor characterized by a modular architecture consisting of extracellular immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic tail (vu2025structureofthe pages 1-3, yeh2026crystalstructureof pages 1-2). Among the Siglec family members, CD33 and Siglec-15 are the smallest, containing only one C-set immunoglobulin (IgC) domain in addition to the N-terminal V-set Ig domain (IgV) (vu2025structureofthe pages 1-3).

Extracellular Domains

Recent structural studies have characterized the CD33 extracellular domain (residues 1-232) in detail (yeh2026crystalstructureof pages 2-4). The N-terminal IgV domain contains the sialoglycan-binding site and is encoded by exon 2, while the IgC domain adopts a C1-type fold characterized by the presence of a βD strand (vu2025structureofthe pages 3-4, vu2025structureofthe pages 4-6). Crystal structures reveal that the IgC domain can homodimerize through intermolecular β-strand pairing, specifically via parallel pairing of βC-βC strands and side-chain packing between βC-βD and βC-βF* strands, burying approximately 808 Ų of surface area (vu2025structureofthe pages 3-4). This dimerization mechanism appears unique to CD33 and Siglec-6 among the CD33-related Siglecs (vu2025structureofthe pages 4-6).

Transmembrane Domain

The transmembrane (TM) domain of CD33 consists of a 21-residue α-helix (Ala265-His285) that appears monomeric in standard lipid bilayers (vu2025structureofthe pages 4-6). The TM helix exhibits a characteristic "thin neck, thick belly" profile, with small side chains (Ala265, Gly266, Ala269, Ala272) in the extracellular leaflet and bulkier residues, including two phenylalanines (Phe279-Phe280), in the core (vu2025structureofthe pages 4-6). The cytoplasmic side features a cluster of positively charged residues (Arg286, Arg287, Lys288, Arg291) creating a distinctive positive patch (vu2025structureofthe pages 4-6).

Cytoplasmic Domain

The cytoplasmic tail of CD33 is dynamically unstructured and contains one immunoreceptor tyrosine-based inhibitory motif (ITIM) and one ITIM-like motif, which are essential for its inhibitory signaling function (vu2025structureofthe pages 3-4, vu2025structureofthe pages 1-3, k2026immunologicalandpathological pages 1-2).

Primary Function: Sialic Acid Recognition

Substrate Specificity

CD33 functions as a lectin receptor that recognizes terminal sialic acids on cell-surface glycans rather than catalyzing enzymatic reactions (vu2025structureofthe pages 1-3, gonzalezgil2021siglecligands pages 1-3). The protein exhibits preference for α2,6-linked sialoglycans, though it can also recognize α2,3-linked structures (vu2025structureofthe pages 1-3, yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4). A specific high-affinity ligand has been identified as the sialylated sulfated trisaccharide Neu5Acα2-3[6SO3]Galβ1-4GlcNAc (vu2025structureofthe pages 1-3).

Molecular Mechanism of Glycan Binding

The sialic acid-binding site is centered on a conserved arginine residue (Arg119) that forms a salt bridge with the sialic acid carboxylate group (yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4). This interaction is further stabilized by an aromatic cluster comprising Phe21, His45, and Tyr127, and by the STKYSYK motif (residues 124-130), which collectively provide the structural basis for the receptor's glycan-binding specificity (yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4).

Physiological Ligands

Physiological ligands for CD33 include keratan sulfate proteoglycans in the brain, which serve as endogenous binding partners in the central nervous system (vu2025structureofthe pages 1-3). Additionally, α2,6-biantennary sialoglycans on hepatitis B virus surface antigen (HBsAg) have been identified as pathogen-derived ligands that engage CD33 to suppress immune responses (yeh2026crystalstructureof pages 2-4).

Cellular Localization and Expression

Subcellular Localization

CD33 is a cell-surface receptor localized to the plasma membrane, where it performs its glycan-recognition functions (vu2025structureofthe pages 1-3). Upon antibody-mediated cross-linking, CD33 can be redistributed to lipid raft domains in the membrane, suggesting that clustering contributes to receptor signaling (vu2025structureofthe pages 3-4, vu2025structureofthe pages 1-3).

Cellular Expression Pattern

CD33 is expressed on cells of the myeloid lineage, including myeloid progenitor cells, monocytes, macrophages, mast cells, dendritic cells, and brain microglia (vu2025structureofthe pages 1-3, gonzalezgil2021siglecligands pages 3-4, wissfeld2021deletionofalzheimers pages 1-2). In the brain, CD33 is prominently expressed on microglial cells, where it plays important roles in regulating innate immune responses to amyloid-β and other pathological stimuli (wissfeld2021deletionofalzheimers pages 1-2, griciuc2020genetherapyfor pages 1-2). The protein is also expressed on cells in hematological malignancies, particularly acute myeloid leukemia, where it serves as a lineage marker (vu2025structureofthe pages 1-3, gonzalezgil2021siglecligands pages 3-4).

Signaling Mechanisms and Biochemical Pathways

ITIM-Mediated Inhibitory Signaling

CD33 functions as an inhibitory immune checkpoint receptor through a well-characterized ITIM-dependent signaling pathway (vu2025structureofthe pages 1-3, k2026immunologicalandpathological pages 1-2). Upon ligand engagement or appropriate receptor clustering, tyrosine residues within the ITIM and ITIM-like motifs become phosphorylated, creating docking sites for SH2 domain-containing protein tyrosine phosphatases (yeh2026crystalstructureof pages 2-4, k2026immunologicalandpathological pages 1-2).

Recruitment of SHP-1 and SHP-2 Phosphatases

The phosphorylated ITIM motifs recruit SHP-1 (encoded by PTPN6) and SHP-2 (encoded by PTPN11) phosphatases to the receptor complex (yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4, k2026immunologicalandpathological pages 1-2, beckers2024cd33andshp1ptpn6 pages 1-2). In human microglia and microglia-like cells, genetic studies have demonstrated genotype-dependent differences in CD33-SHP-1 interaction, with the Alzheimer's disease risk variant affecting this critical signaling partnership (beckers2024cd33andshp1ptpn6 pages 1-2). The recruited phosphatases dephosphorylate activating signaling molecules, thereby attenuating downstream pathways and suppressing cellular activation (k2026immunologicalandpathological pages 1-2).

Antagonism of Activating Pathways

CD33 signaling directly opposes immunoreceptor tyrosine-based activation motif (ITAM)/DAP12-associated pathways, including those mediated by TREM2 and other activating receptors (wissfeld2021deletionofalzheimers pages 1-2, k2026immunologicalandpathological pages 1-2). In microglia, deletion or functional disruption of CD33 leads to increased phosphorylation of spleen tyrosine kinase (SYK) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), indicating relief from CD33-mediated inhibition (wissfeld2021deletionofalzheimers pages 1-2). This antagonistic relationship positions CD33 as a key negative regulator of myeloid cell activation and phagocytosis.

Biological Functions

Immune Regulation and Self-Recognition

The primary biological function of CD33 is to serve as an inhibitory immune checkpoint that recognizes self-associated sialoglycans and dampens myeloid cell activation (vu2025structureofthe pages 1-3, laubli2022targetingthesiglec–sialic pages 1-1). By recognizing terminal sialic acids on self-glycans, CD33 contributes to immune self/non-self discrimination and prevents excessive immune activation (vu2025structureofthe pages 1-3, gonzalezgil2021siglecligands pages 1-3).

Regulation of Phagocytosis

CD33 potently inhibits phagocytosis in myeloid cells, including microglia (wissfeld2021deletionofalzheimers pages 1-2, griciuc2020genetherapyfor pages 1-2). Loss of CD33 function or genetic knockout increases the phagocytosis of aggregated amyloid-β1-42 peptides, bacterial particles, and cellular debris (wissfeld2021deletionofalzheimers pages 1-2). This inhibitory effect on phagocytosis is mediated through the ITIM-dependent recruitment of phosphatases that counteract activating signals required for efficient phagocytosis.

Control of Inflammatory Responses

Deletion of CD33 or knockdown of its signaling partner PTPN6/SHP-1 leads to constitutive activation of inflammation-related gene transcription pathways (wissfeld2021deletionofalzheimers pages 1-2). CD33 knockout human macrophages and microglia show increased transcript levels of pro-inflammatory cytokines including IL-1β, IL-8, and IL-10, along with upregulation of the AD-associated phosphatase INPP5D (wissfeld2021deletionofalzheimers pages 1-2). These findings demonstrate that CD33 normally suppresses inflammatory gene expression in myeloid cells.

Alternative Isoforms and Functional Consequences

CD33 Isoform Structure

Human CD33 undergoes alternative splicing to generate two major isoforms: the full-length CD33M containing all extracellular domains and the short isoform CD33m (also called CD33ΔE2), which lacks exon 2 and therefore the sialic acid-binding IgV domain (wissfeld2021deletionofalzheimers pages 1-2, beckers2024cd33andshp1ptpn6 pages 1-2). The relative expression of these isoforms has important functional and disease-relevant consequences.

Functional Differences Between Isoforms

The full-length CD33M isoform is generally inhibitory, suppressing microglial phagocytosis, migration, and proliferation while promoting cell adhesion (wissfeld2021deletionofalzheimers pages 1-2). In contrast, the short CD33m isoform exhibits gain-of-function properties, enhancing phagocytosis and proliferation while inhibiting cell adhesion (wissfeld2021deletionofalzheimers pages 1-2). Importantly, CD33m can increase phagocytosis of Aβ1-42 without the detrimental oxidative burst observed with complete CD33 knockout, suggesting a more balanced functional profile (wissfeld2021deletionofalzheimers pages 1-2).

Disease Relevance and Therapeutic Implications

Alzheimer's Disease

CD33 is a validated genetic risk factor for late-onset Alzheimer's disease (wissfeld2021deletionofalzheimers pages 1-2, griciuc2020genetherapyfor pages 1-2, beckers2024cd33andshp1ptpn6 pages 1-2). The rs3865444C risk allele is associated with increased surface expression of full-length CD33 on myeloid cells, reduced phagocytosis of amyloid-β, and greater amyloid plaque accumulation in the brain (beckers2024cd33andshp1ptpn6 pages 1-2). Conversely, the protective haplotype involving the rs12459419T single nucleotide polymorphism promotes exon 2 skipping, leading to increased expression of the CD33m isoform and reduced AD risk (wissfeld2021deletionofalzheimers pages 1-2, beckers2024cd33andshp1ptpn6 pages 1-2).

CD33 is upregulated on microglial cells in post-mortem AD patient brains, and high levels of CD33 correlate positively with amyloid-β burden and plaque load (wissfeld2021deletionofalzheimers pages 1-2, griciuc2020genetherapyfor pages 1-2). Gene therapy approaches using adeno-associated virus (AAV) vectors encoding artificial microRNA targeting CD33 have shown promise in mouse models, reducing CD33 mRNA, soluble Aβ40 and Aβ42 levels, amyloid plaque burden, and neuroinflammatory markers when administered early in disease progression (griciuc2020genetherapyfor pages 1-2).

Acute Myeloid Leukemia

CD33 serves as a well-established lineage marker on myeloid leukemias and has been successfully exploited as a therapeutic target in acute myeloid leukemia (AML) (vu2025structureofthe pages 1-3, laubli2022targetingthesiglec–sialic pages 1-1, gonzalezgil2021siglecligands pages 3-4). Antibody-drug conjugates targeting CD33, such as gemtuzumab ozogamicin, deliver cytotoxic payloads specifically to CD33-expressing malignant cells, demonstrating the clinical utility of targeting this receptor in hematologic malignancies (laubli2022targetingthesiglec–sialic pages 1-1).

Viral Immune Evasion

CD33 has been implicated as an inhibitory receptor exploited by chronic hepatitis B virus (HBV) infection (yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4). The α2,6-biantennary sialoglycans present on HBV surface antigen (HBsAg) engage CD33 on myeloid cells, triggering ITIM phosphorylation and SHP-1/2 recruitment, thereby dampening antiviral immune responses and promoting immune tolerance (yeh2026crystalstructureof pages 2-4). Monoclonal antibodies that block CD33-HBsAg interactions can restore immune function in this context (yeh2026crystalstructureof pages 2-4).

Summary

Aspect	Key findings for human CD33 (SIGLEC3; UniProt P20138)	Evidence/Citation
Verified identity	CD33 is the human myeloid cell surface antigen also called Siglec-3, a member of the CD33-related Siglec family within the immunoglobulin superfamily; this matches the UniProt target description and distinguishes it from unrelated genes.	(vu2025structureofthe pages 1-3, laubli2022targetingthesiglec–sialic pages 2-3)
Protein class and overall architecture	Single-pass type I transmembrane receptor with an extracellular region containing 2 Ig-like domains, a transmembrane helix, and a cytoplasmic tail. The extracellular domains are an N-terminal V-set Ig domain for glycan recognition and one C-set/C2-set Ig-like domain contributing to structure and receptor organization.	(vu2025structureofthe pages 1-3, yeh2026crystalstructureof pages 1-2, k2026immunologicalandpathological pages 1-2)
Structural/domain details	CD33 is among the smallest Siglecs because it contains only one IgC domain after the IgV domain. Recent structural work supports an IgC1 homodimerization interface, a 21-residue mostly monomeric transmembrane helix, and a dynamically unstructured cytosolic domain.	(vu2025structureofthe pages 1-3, vu2025structureofthe pages 3-4, vu2025structureofthe pages 4-6)
Extracellular domain boundaries used experimentally	A recent structural study expressed human CD33 extracellular domain as residues 1-232, supporting the two-domain ectodomain organization used in biochemical and crystallographic analyses.	(yeh2026crystalstructureof pages 2-4)
Sialic acid-binding site	The glycan-binding site is centered on a conserved Arg119 that ligates the sialic acid carboxylate. Binding is further stabilized by an aromatic cluster including Phe21, His45, and Tyr127 and by the STKYSYK motif spanning residues 124-130.	(yeh2026crystalstructureof pages 1-2)
Glycan/substrate specificity	CD33 recognizes terminal sialic acids on sialoglycans rather than catalyzing a reaction. Siglecs in general discriminate among α2-3, α2-6, and α2-8 linkages and underlying glycan context; for CD33, available structural and functional evidence supports preference for α2-6-linked sialoglycans and also binding to the sulfated sialylated trisaccharide Neu5Acα2-3[6SO3]Galβ1-4GlcNAc.	(gonzalezgil2021siglecligands pages 1-3, vu2025structureofthe pages 1-3, yeh2026crystalstructureof pages 1-2)
Physiologic and disease-relevant ligands	Reported physiological ligands include keratan sulfate proteoglycans in the brain. In chronic hepatitis B work, α2,6-biantennary sialoglycans on HBsAg bind CD33 directly and trigger inhibitory signaling.	(vu2025structureofthe pages 1-3, yeh2026crystalstructureof pages 2-4)
Ligand-binding mode	CD33 recognizes self-associated sialoglycans as part of immune self/non-self discrimination. Multivalency and receptor clustering are likely important for productive signaling.	(vu2025structureofthe pages 1-3, laubli2022targetingthesiglec–sialic pages 1-1, gonzalezgil2021siglecligands pages 1-3)
Cellular localization	Cell-surface receptor on the plasma membrane of myeloid-lineage cells; antibody cross-linking can relocalize CD33 to lipid raft membrane domains.	(vu2025structureofthe pages 1-3, vu2025structureofthe pages 3-4)
Cell-type expression	Expressed on myeloid progenitors, monocytes, macrophages, mast cells, dendritic cells, and brain microglia; disease/atlas-style summaries also list leukemias and myelodysplastic syndromes among contexts where these expressing cells are clinically important.	(vu2025structureofthe pages 1-3, gonzalezgil2021siglecligands pages 3-4)
Cytoplasmic signaling motifs	CD33 contains one ITIM and one ITIM-like motif in its cytoplasmic tail; inhibitory Siglecs use these phosphotyrosine motifs to recruit phosphatases after receptor engagement.	(vu2025structureofthe pages 1-3, k2026immunologicalandpathological pages 1-2)
Proximal signaling mechanism	Upon ligand engagement or appropriate crosslinking, CD33 ITIM motifs become phosphorylated and recruit SHP-1 and/or SHP-2 phosphatases, attenuating activating pathways and suppressing cell activation. HBV-associated studies specifically describe ITIM phosphorylation followed by SHP-1/2 recruitment.	(yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4, k2026immunologicalandpathological pages 1-2)
SHP phosphatase coupling	Human AD-focused work emphasizes CD33-SHP-1/PTPN6 interaction, including genotype-dependent differences in microglia-like cells, while broader Siglec studies and HBV work support SHP-1 and SHP-2 recruitment capability.	(beckers2024cd33andshp1ptpn6 pages 1-2, yeh2026crystalstructureof pages 1-2, k2026immunologicalandpathological pages 1-2)
Relationship to activating pathways	CD33 functions as an inhibitory checkpoint that counterbalances ITAM/DAP12-SYK/MAPK-type activation pathways. In microglia, CD33 loss or signaling disruption increases SYK and ERK1/2 phosphorylation and enhances phagocytosis, consistent with antagonism of activating receptors such as TREM2-associated pathways.	(wissfeld2021deletionofalzheimers pages 1-2, k2026immunologicalandpathological pages 1-2)
Primary biological function	Immune inhibitory receptor that senses sialoglycans and dampens myeloid-cell activation. In the CNS, CD33 modulates microglial responses, including phagocytosis of amyloid-β and inflammatory output; in peripheral myeloid cells it contributes to inhibitory checkpoint control.	(vu2025structureofthe pages 1-3, wissfeld2021deletionofalzheimers pages 1-2, griciuc2020genetherapyfor pages 1-2)
Functional consequences of reduced CD33 signaling	CD33 knockout or exon-2-deleted CD33 expression in human macrophages/microglia increases inflammatory-pathway transcription, SYK and ERK1/2 phosphorylation, and phagocytosis of aggregated Aβ1-42 and bacterial particles; oxidative burst rises after knockout but not necessarily after the short isoform.	(wissfeld2021deletionofalzheimers pages 1-2)
Alzheimer’s disease genetics	CD33 is an AD susceptibility locus. The rs3865444C risk allele is associated with increased surface density/full-length CD33 on myeloid cells and reduced Aβ phagocytosis, while the protective haplotype involving rs12459419T favors exon 2 skipping and production of the short isoform lacking the canonical sialic acid-binding IgV domain.	(beckers2024cd33andshp1ptpn6 pages 1-2, wissfeld2021deletionofalzheimers pages 1-2)
AD isoforms and function	Full-length CD33M is generally inhibitory and associated with increased Aβ burden, whereas the short isoform CD33m/CD33ΔE2 is AD-protective and can enhance phagocytosis or plaque compaction despite lacking the canonical exon 2-encoded binding domain.	(wissfeld2021deletionofalzheimers pages 1-2)
Therapeutic relevance in AD	AAV-mediated knockdown of CD33 in APP/PS1 mice reduced CD33 mRNA, soluble Aβ40/Aβ42, plaque burden, and neuroinflammatory readouts, supporting CD33 as a therapeutic target for microglial reprogramming in AD.	(griciuc2020genetherapyfor pages 1-2)
Hematologic malignancy relevance	CD33 is a lineage marker on myeloid leukemias and a validated therapeutic target in acute myeloid leukemia; this clinical use reflects stable cell-surface expression on malignant myeloid cells rather than an enzymatic activity.	(vu2025structureofthe pages 1-3, laubli2022targetingthesiglec–sialic pages 1-1, gonzalezgil2021siglecligands pages 3-4)
Additional disease context	CD33 has also been implicated as an inhibitory receptor exploited by HBV, where viral HBsAg-associated α2,6 sialoglycans engage CD33 to promote immune tolerance in myeloid cells.	(yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4)

Table: This table summarizes the verified identity, structure, ligand specificity, localization, signaling mechanism, core functions, and disease relevance of human CD33/Siglec-3. It is useful as a compact evidence map for functional annotation of the gene product.

CD33 (Siglec-3, UniProt P20138) is a myeloid cell surface receptor belonging to the sialic acid-binding immunoglobulin-like lectin family in humans. The protein functions as an inhibitory immune checkpoint that recognizes terminal sialic acids on self-glycans through its N-terminal V-set immunoglobulin domain, with binding specificity centered on a conserved Arg119 residue and preferential recognition of α2,6-linked sialoglycans (vu2025structureofthe pages 1-3, yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4). CD33 is expressed on myeloid lineage cells including monocytes, macrophages, and brain microglia, where it localizes to the cell surface and can redistribute to lipid raft domains upon clustering (vu2025structureofthe pages 3-4, vu2025structureofthe pages 1-3).

The primary signaling mechanism involves ITIM-mediated recruitment of SHP-1 and SHP-2 phosphatases, which dephosphorylate activating signaling molecules and suppress cellular responses (yeh2026crystalstructureof pages 1-2, yeh2026crystalstructureof pages 2-4, k2026immunologicalandpathological pages 1-2, beckers2024cd33andshp1ptpn6 pages 1-2). This inhibitory signaling opposes ITAM/DAP12-associated activation pathways such as TREM2, positioning CD33 as a key negative regulator of microglial phagocytosis and inflammatory responses (wissfeld2021deletionofalzheimers pages 1-2, k2026immunologicalandpathological pages 1-2). CD33 undergoes alternative splicing to produce functionally distinct isoforms, with the full-length CD33M being inhibitory and the exon 2-deleted CD33m isoform exhibiting gain-of-function properties including enhanced phagocytosis (wissfeld2021deletionofalzheimers pages 1-2).

CD33 plays critical roles in Alzheimer's disease pathogenesis, where genetic variants modulating isoform expression influence amyloid-β clearance and AD risk, and in acute myeloid leukemia, where it serves as a validated therapeutic target (wissfeld2021deletionofalzheimers pages 1-2, griciuc2020genetherapyfor pages 1-2, beckers2024cd33andshp1ptpn6 pages 1-2). Understanding CD33's structure, substrate specificity, signaling mechanisms, and disease associations provides a foundation for developing targeted immunotherapies in neurodegeneration and cancer.

References

(vu2025structureofthe pages 1-3): Han N. Vu, Alan J. Situ, Xuhang Dai, and Tobias S. Ulmer. Structure of the cd33 receptor and implications for the siglec family. Biochemistry, 64:1450-1462, Mar 2025. URL: https://doi.org/10.1021/acs.biochem.4c00864, doi:10.1021/acs.biochem.4c00864. This article has 6 citations and is from a peer-reviewed journal.
(laubli2022targetingthesiglec–sialic pages 1-1): Heinz Läubli, Sam C. Nalle, and Daniel Maslyar. Targeting the siglec–sialic acid immune axis in cancer: current and future approaches. Cancer Immunology Research, 10:1423-1432, Oct 2022. URL: https://doi.org/10.1158/2326-6066.cir-22-0366, doi:10.1158/2326-6066.cir-22-0366. This article has 114 citations and is from a domain leading peer-reviewed journal.
(laubli2022targetingthesiglec–sialic pages 2-3): Heinz Läubli, Sam C. Nalle, and Daniel Maslyar. Targeting the siglec–sialic acid immune axis in cancer: current and future approaches. Cancer Immunology Research, 10:1423-1432, Oct 2022. URL: https://doi.org/10.1158/2326-6066.cir-22-0366, doi:10.1158/2326-6066.cir-22-0366. This article has 114 citations and is from a domain leading peer-reviewed journal.
(yeh2026crystalstructureof pages 1-2): Yi-Hung Yeh, Min-Guan Lin, Pei-Shan Sung, Shie-Liang Hsieh, and Chwan-Deng Hsiao. Crystal structure of the cd33/fab-10c8 complex elucidates the mechanism of antibody antagonism in hbv-induced immunosuppression. Journal of Biomedical Science, May 2026. URL: https://doi.org/10.1186/s12929-026-01248-9, doi:10.1186/s12929-026-01248-9. This article has 0 citations and is from a domain leading peer-reviewed journal.
(yeh2026crystalstructureof pages 2-4): Yi-Hung Yeh, Min-Guan Lin, Pei-Shan Sung, Shie-Liang Hsieh, and Chwan-Deng Hsiao. Crystal structure of the cd33/fab-10c8 complex elucidates the mechanism of antibody antagonism in hbv-induced immunosuppression. Journal of Biomedical Science, May 2026. URL: https://doi.org/10.1186/s12929-026-01248-9, doi:10.1186/s12929-026-01248-9. This article has 0 citations and is from a domain leading peer-reviewed journal.
(vu2025structureofthe pages 3-4): Han N. Vu, Alan J. Situ, Xuhang Dai, and Tobias S. Ulmer. Structure of the cd33 receptor and implications for the siglec family. Biochemistry, 64:1450-1462, Mar 2025. URL: https://doi.org/10.1021/acs.biochem.4c00864, doi:10.1021/acs.biochem.4c00864. This article has 6 citations and is from a peer-reviewed journal.
(vu2025structureofthe pages 4-6): Han N. Vu, Alan J. Situ, Xuhang Dai, and Tobias S. Ulmer. Structure of the cd33 receptor and implications for the siglec family. Biochemistry, 64:1450-1462, Mar 2025. URL: https://doi.org/10.1021/acs.biochem.4c00864, doi:10.1021/acs.biochem.4c00864. This article has 6 citations and is from a peer-reviewed journal.
(k2026immunologicalandpathological pages 1-2): Lakshmi K and Vino Sundararajan. Immunological and pathological roles of siglecs: a molecular review. Frontiers in Immunology, May 2026. URL: https://doi.org/10.3389/fimmu.2026.1826359, doi:10.3389/fimmu.2026.1826359. This article has 0 citations and is from a peer-reviewed journal.
(gonzalezgil2021siglecligands pages 1-3): Anabel Gonzalez-Gil and Ronald L. Schnaar. Siglec ligands. Cells, 10:1260, May 2021. URL: https://doi.org/10.3390/cells10051260, doi:10.3390/cells10051260. This article has 131 citations.
(gonzalezgil2021siglecligands pages 3-4): Anabel Gonzalez-Gil and Ronald L. Schnaar. Siglec ligands. Cells, 10:1260, May 2021. URL: https://doi.org/10.3390/cells10051260, doi:10.3390/cells10051260. This article has 131 citations.
(wissfeld2021deletionofalzheimers pages 1-2): Jannis Wißfeld, Ichiro Nozaki, Mona Mathews, Tamara Raschka, Christian Ebeling, Veit Hornung, Oliver Brüstle, and Harald Neumann. Deletion of alzheimer's disease‐associated cd33 results in an inflammatory human microglia phenotype. Glia, 69:1393-1412, Feb 2021. URL: https://doi.org/10.1002/glia.23968, doi:10.1002/glia.23968. This article has 111 citations and is from a domain leading peer-reviewed journal.
(griciuc2020genetherapyfor pages 1-2): Ana Griciuc, Anthony N Federico, Jeyashree Natasan, Angela M Forte, Danielle McGinty, Huong Nguyen, Adrienn Volak, Stanley LeRoy, Sheetal Gandhi, Eli P Lerner, Eloise Hudry, Rudolph E Tanzi, and Casey A Maguire. Gene therapy for alzheimer's disease targeting cd33 reduces amyloid beta accumulation and neuroinflammation. Human molecular genetics, 29:2920-2935, Aug 2020. URL: https://doi.org/10.1093/hmg/ddaa179, doi:10.1093/hmg/ddaa179. This article has 151 citations and is from a domain leading peer-reviewed journal.
(beckers2024cd33andshp1ptpn6 pages 1-2): Lien Beckers, Mamunur Rashid, Annie J. Lee, Zena K. Chatila, Kirstin A. Tamucci, Ryan C. Talcoff, Jennifer L. Hall, David A. Bennett, Badri N. Vardarajan, and Elizabeth M. Bradshaw. Cd33 and shp-1/ptpn6 interaction in alzheimer’s disease. Genes, 15:1204, Sep 2024. URL: https://doi.org/10.3390/genes15091204, doi:10.3390/genes15091204. This article has 8 citations.

Artifacts

Edison artifact artifact-00

Citations

vu2025structureofthe pages 1-3
yeh2026crystalstructureof pages 2-4
vu2025structureofthe pages 3-4
vu2025structureofthe pages 4-6
k2026immunologicalandpathological pages 1-2
wissfeld2021deletionofalzheimers pages 1-2
griciuc2020genetherapyfor pages 1-2
yeh2026crystalstructureof pages 1-2
gonzalezgil2021siglecligands pages 1-3
gonzalezgil2021siglecligands pages 3-4
6SO3
https://doi.org/10.1021/acs.biochem.4c00864,
https://doi.org/10.1158/2326-6066.cir-22-0366,
https://doi.org/10.1186/s12929-026-01248-9,
https://doi.org/10.3389/fimmu.2026.1826359,
https://doi.org/10.3390/cells10051260,
https://doi.org/10.1002/glia.23968,
https://doi.org/10.1093/hmg/ddaa179,
https://doi.org/10.3390/genes15091204,

📚 Additional Documentation

Notes

(CD33-notes.md)

CD33 curation notes

2026-06-19

Deep-research attempt with just deep-research-falcon human CD33 --fallback perplexity-lite timed out after 180 seconds with no generated research artifact, so this manual review uses cached UniProt, GOA, Reactome, PANTHER family, and publication evidence.
CD33/Siglec-3 is a myeloid-lineage type I membrane Siglec and inhibitory receptor. UniProt summarizes expression in monocytic/myeloid cells and brain microglia, cell-surface CD33M localization, and an intracellular/peroxisomal CD33m splice isoform.
Sialic acid binding and cell-cell interaction are core. The founding ligand study reports that CD33 recognizes sialylated glycans and concludes that "CD33 can function as a sialic acid-dependent cell adhesion molecule" PMID:7718872.
CD33 inhibitory signaling is mediated by ITIM phosphorylation and SHP-1/SHP-2 recruitment. The JBC study reports that "Phosphorylated CD33 recruited both the protein-tyrosine phosphatases, SHP-1 and SHP-2" PMID:10206955.
Functional inhibitory receptor evidence is direct: CD33 down-regulates CD64/FcgammaRI calcium signaling, and dominant-negative SHP-1 blocks this effect PMID:10887109.
CD33 monocyte repressor activity depends on sialic acid recognition and PI3K-linked intracellular signaling. The cached abstract says lower CD33 surface expression caused spontaneous cytokine production, neuraminidase increased IL-1 beta, and ligand addition reversed the effect PMID:15597323.
CD33 engagement can inhibit proliferation/survival in normal or leukemic myeloid contexts, supporting the negative regulation of cell population proliferation annotation as part of inhibitory receptor biology PMID:10611343.
C1q interaction is biologically meaningful but should not be left as generic protein binding if a more specific representation becomes available. The full text reports that C1q/gC1q interacts with CD33 and activates inhibitory motifs PMID:28325905.
CD33m peroxisome localization is isoform-specific and Alzheimer-relevant but not the core cell-surface receptor function. The cached abstract says CD33m lacks the sialic acid-binding domain and "does not localize to cell surfaces; instead, it accumulates in peroxisomes" PMID:28747436.
The tau/protein secretion annotation from PMID:27044754 was marked UNDECIDED because the cached abstract names FRMD4A as the functional tau-secretion hit and does not expose the CD33-specific screen result PMID:27044754.
Generic protein binding annotations were marked over-annotated except where a specific term exists (protein phosphatase binding); high-throughput interactome hits do not define CD33 function without more specific biological context.

2026-06-20 Second-Pass Review Notes

Second-pass audit confirmed the existing action calls and reference-review
coverage. No YAML changes were needed in this pass.

The single UNDECIDED annotation remains GO:0050714 positive regulation of
protein secretion from PMID:27044754. The cached abstract identifies FRMD4A as
the functional tau-release hit and does not show the CD33-specific evidence
behind the IMP annotation. Because the annotation is experimental and the local
cache is abstract-only for the relevant claim, it should remain UNDECIDED rather
than be removed.

The core function remains CD33/Siglec-3 sialic-acid binding at the myeloid cell
surface plus ITIM-dependent SHP-1/SHP-2 recruitment and inhibitory signaling.
The Alzheimer-relevant CD33m splice isoform should be handled as isoform- and
localization-specific biology rather than used to redefine the core CD33M
surface inhibitory receptor function.

Falcon deep research integration (2026-06-21)

A grounded Falcon (Edison) deep-research report (CD33-deep-research-falcon.md, ~19 citations) was integrated; it strongly corroborates the existing review's core model (myeloid sialic-acid-binding Ig-type lectin / ITIM-bearing inhibitory receptor recruiting SHP-1/SHP-2) and adds structural, ligand, and disease-genetics detail without contradicting any existing action call. All Falcon-sourced citations below are not yet independently verified against full text.

NEW or REFINED findings beyond existing notes/review:

Sialic-acid-binding site is centered on a conserved Arg119 forming a salt bridge to the sialic acid carboxylate, with an aromatic cluster (Phe21, His45, Tyr127) and the STKYSYK motif (residues 124-130); preference for alpha-2,6-linked sialoglycans, and a defined high-affinity ligand Neu5Ac-alpha2-3[6SO3]Gal-beta1-4GlcNAc [Yeh et al. 2026 J Biomed Sci, DOI:10.1186/s12929-026-01248-9; Vu et al. 2025 Biochemistry 64:1450-1462, DOI:10.1021/acs.biochem.4c00864] (not yet independently verified against full text).
Structural architecture: smallest-Siglec two-domain ectodomain (IgV + single IgC), an IgC1 homodimerization interface (~808 sq A, shared only with Siglec-6), a 21-residue mostly monomeric TM helix, and a dynamically unstructured cytoplasmic tail with one ITIM + one ITIM-like motif [Vu et al. 2025 Biochemistry, DOI:10.1021/acs.biochem.4c00864] (not yet independently verified against full text).
Physiological/pathogen ligands: keratan sulfate proteoglycans as endogenous CNS ligands, and alpha-2,6-biantennary sialoglycans on hepatitis B surface antigen (HBsAg) as a pathogen-derived ligand that engages CD33 to drive ITIM/SHP-1/2-mediated immune suppression (a viral immune-evasion axis not in the current review) [Yeh et al. 2026 J Biomed Sci, DOI:10.1186/s12929-026-01248-9; Vu et al. 2025 Biochemistry] (not yet independently verified against full text).
Microglial signaling context: CD33 antagonizes ITAM/DAP12-SYK/ERK activating pathways (e.g. TREM2-associated); CD33 loss/disruption raises SYK and ERK1/2 phosphorylation and increases phagocytosis of Abeta1-42 and bacterial particles, with constitutive inflammatory gene transcription (IL-1beta, IL-8, IL-10, INPP5D) on knockout [Wissfeld et al. 2021 Glia 69:1393-1412, DOI:10.1002/glia.23968] (not yet independently verified against full text).
Alzheimer-risk allele biology made explicit: rs3865444C risk allele associates with increased full-length CD33 surface density and reduced Abeta phagocytosis, whereas the protective rs12459419T promotes exon-2 skipping to the CD33m / CD33dE2 isoform lacking the IgV sialic-acid-binding domain [Beckers et al. 2024 Genes 15:1204, DOI:10.3390/genes15091204; Wissfeld et al. 2021 Glia, DOI:10.1002/glia.23968] (not yet independently verified against full text).
REFINED isoform view: CD33m is reported not only as cell-surface-diverted but as a gain-of-function isoform (enhanced phagocytosis/proliferation, reduced adhesion, Abeta uptake without the oxidative burst seen with full knockout); this nuances the existing notes' loss-of-function/peroxisomal framing [Wissfeld et al. 2021 Glia] (not yet independently verified against full text).
Therapeutic context: AAV-delivered artificial-miRNA knockdown of CD33 in APP/PS1 mice reduced CD33 mRNA, soluble Abeta40/42, plaque burden, and neuroinflammation [Griciuc et al. 2020 Hum Mol Genet 29:2920-2935, DOI:10.1093/hmg/ddaa179]; CD33 as a validated AML antibody-drug-conjugate target (gemtuzumab ozogamicin) [Laubli et al. 2022 Cancer Immunol Res 10:1423-1432, DOI:10.1158/2326-6066.cir-22-0366] (not yet independently verified against full text).

Discrepancies / annotations to revisit:

No direct contradiction with existing annotations or action calls. The report reinforces ACCEPT for GO:0033691 (sialic acid binding), GO:0019903 (protein phosphatase binding), GO:0008160 (protein tyrosine phosphatase activator activity), GO:0002765 (immune response-inhibiting signal transduction), and the negative-regulation/cytokine terms.
The HBsAg/HBV immune-suppression axis and the microglial TREM2/SYK-ERK antagonism are not captured by any current GO term in the review; these are candidate new-term / process directions to consider (e.g. negative regulation of microglial phagocytosis or innate immune response) but are based on single Falcon-sourced reports and should be verified before any term is added.
The report does not bear on the one UNDECIDED annotation (GO:0050714 positive regulation of protein secretion, PMID:27044754); that remains UNDECIDED pending CD33-specific full-text evidence.

📄 View Raw YAML

id: P20138
gene_symbol: CD33
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'CD33 encodes Siglec-3, a type I transmembrane sialic-acid-binding immunoglobulin-like
  lectin expressed mainly on myeloid cells, including monocytes, myeloid progenitors, and
  brain microglia. Full-length CD33M acts at the plasma membrane as an inhibitory immune receptor:
  its extracellular Ig-like domain binds sialylated glycans, while ligand engagement or receptor
  crosslinking promotes ITIM phosphorylation in the cytoplasmic tail and recruitment of the
  phosphatases SHP-1/PTPN6 and SHP-2/PTPN11. Through these signaling modules, CD33 dampens
  myeloid and monocyte activation, cytokine production, calcium signaling, Fc-gamma receptor
  responses, and proliferation. A shorter CD33m splice isoform lacking the sialic-acid-binding
  domain is largely diverted from the cell surface to an intracellular/peroxisomal pool and
  is relevant to Alzheimer disease genetics.'
alternative_products:
- name: CD33M
  id: P20138-1
- name: '3'
  id: P20138-2
  sequence_note: VSP_045364
- name: CD33m
  id: P20138-3
  sequence_note: VSP_046172
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'CD33 mediates sialic-acid-dependent cell-cell interactions, but the broad cell
      adhesion term should be replaced with the more specific cell-cell adhesion term already
      supported for CD33.'
    action: MODIFY
    reason: The sialoadhesin/Siglec evidence supports sialic-acid-dependent cell-cell 
      adhesion rather than a broad adhesion process.
    proposed_replacement_terms:
    - id: GO:0098609
      label: cell-cell adhesion
- term:
    id: GO:0033691
    label: sialic acid binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: 'Sialic acid binding is the defining extracellular Siglec molecular function
      of CD33.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Peroxisome localization is supported for the CD33m splice isoform that lacks
      the sialic-acid-binding domain and is diverted away from the cell surface, especially
      in Alzheimer disease genetics context.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      reflects isoform-specific intracellular localization, receptor 
      biosynthesis/trafficking, or neutrophil granule context rather than the main 
      cell-surface inhibitory Siglec role.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10206955
  qualifier: enables
  review:
    summary: 'These studies support SHP-1/SHP-2 interaction, which is better captured by the
      specific protein phosphatase binding annotation.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10556798
  qualifier: enables
  review:
    summary: 'These studies support SHP-1/SHP-2 interaction, which is better captured by the
      specific protein phosphatase binding annotation.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17947393
  qualifier: enables
  review:
    summary: 'This protein interaction annotation is too generic or high-throughput to clarify
      CD33 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24216507
  qualifier: enables
  review:
    summary: 'This protein interaction annotation is too generic or high-throughput to clarify
      CD33 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: 'This protein interaction annotation is too generic or high-throughput to clarify
      CD33 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: 'This protein interaction annotation is too generic or high-throughput to clarify
      CD33 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32822567
  qualifier: enables
  review:
    summary: 'This protein interaction annotation is too generic or high-throughput to clarify
      CD33 molecular function.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0005777
    label: peroxisome
  evidence_type: EXP
  original_reference_id: PMID:28747436
  qualifier: located_in
  review:
    summary: 'Peroxisome localization is supported for the CD33m splice isoform that lacks
      the sialic-acid-binding domain and is diverted away from the cell surface, especially
      in Alzheimer disease genetics context.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      reflects isoform-specific intracellular localization, receptor 
      biosynthesis/trafficking, or neutrophil granule context rather than the main 
      cell-surface inhibitory Siglec role.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:10611343
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:28747436
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0008160
    label: protein tyrosine phosphatase activator activity
  evidence_type: IMP
  original_reference_id: PMID:10556798
  qualifier: enables
  review:
    summary: 'Phosphorylated CD33 ITIM motifs recruit and activate SHP-1/SHP-2 protein tyrosine
      phosphatases, forming the core inhibitory signaling mechanism.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0019903
    label: protein phosphatase binding
  evidence_type: IPI
  original_reference_id: PMID:10556798
  qualifier: enables
  review:
    summary: 'Phosphorylated CD33 ITIM motifs recruit and activate SHP-1/SHP-2 protein tyrosine
      phosphatases, forming the core inhibitory signaling mechanism.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0038094
    label: Fc-gamma receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:10556798
  qualifier: involved_in
  review:
    summary: 'CD33 ITIM/SHP signaling down-regulates Fc-gamma receptor-induced calcium signaling,
      so this pathway context is consistent with the inhibitory receptor role.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:21278227
  qualifier: located_in
  review:
    summary: 'This intracellular or granule-membrane localization is compatible with CD33
      biosynthesis, trafficking, or myeloid granule context, but it is not the main functional
      site of full-length CD33M inhibitory signaling.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      reflects isoform-specific intracellular localization, receptor 
      biosynthesis/trafficking, or neutrophil granule context rather than the main 
      cell-surface inhibitory Siglec role.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:21278227
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0150102
    label: negative regulation of monocyte activation
  evidence_type: IDA
  original_reference_id: PMID:15597323
  qualifier: involved_in
  review:
    summary: 'This immune-inhibitory/monocyte-cytokine regulation annotation reflects the
      core CD33 function in restraining myeloid cell activation.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0032691
    label: negative regulation of interleukin-1 beta production
  evidence_type: IMP
  original_reference_id: PMID:15597323
  qualifier: involved_in
  review:
    summary: 'This immune-inhibitory/monocyte-cytokine regulation annotation reflects the
      core CD33 function in restraining myeloid cell activation.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0032717
    label: negative regulation of interleukin-8 production
  evidence_type: IMP
  original_reference_id: PMID:15597323
  qualifier: involved_in
  review:
    summary: 'This immune-inhibitory/monocyte-cytokine regulation annotation reflects the
      core CD33 function in restraining myeloid cell activation.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0032720
    label: negative regulation of tumor necrosis factor production
  evidence_type: IMP
  original_reference_id: PMID:15597323
  qualifier: involved_in
  review:
    summary: 'This immune-inhibitory/monocyte-cytokine regulation annotation reflects the
      core CD33 function in restraining myeloid cell activation.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0033691
    label: sialic acid binding
  evidence_type: IMP
  original_reference_id: PMID:15597323
  qualifier: enables
  review:
    summary: 'Sialic acid binding is the defining extracellular Siglec molecular function
      of CD33.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0098609
    label: cell-cell adhesion
  evidence_type: IMP
  original_reference_id: PMID:10206955
  qualifier: involved_in
  review:
    summary: 'CD33 can mediate sialic-acid-dependent cell-cell adhesion/interactions when
      expressed at the plasma membrane.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0033691
    label: sialic acid binding
  evidence_type: IMP
  original_reference_id: PMID:7718872
  qualifier: enables
  review:
    summary: 'Sialic acid binding is the defining extracellular Siglec molecular function
      of CD33.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0098609
    label: cell-cell adhesion
  evidence_type: IMP
  original_reference_id: PMID:7718872
  qualifier: involved_in
  review:
    summary: 'CD33 can mediate sialic-acid-dependent cell-cell adhesion/interactions when
      expressed at the plasma membrane.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0050714
    label: positive regulation of protein secretion
  evidence_type: IMP
  original_reference_id: PMID:27044754
  qualifier: involved_in
  review:
    summary: 'The cached abstract for the tau-release screen names FRMD4A as the functional
      hit and does not expose the CD33-specific data behind this IMP annotation.'
    action: UNDECIDED
    reason: Use UNDECIDED because the supporting publication is abstract-only in the 
      cache and the accessible abstract does not verify the CD33-specific protein 
      secretion result.
- term:
    id: GO:0002765
    label: immune response-inhibiting signal transduction
  evidence_type: IDA
  original_reference_id: PMID:10887109
  qualifier: involved_in
  review:
    summary: 'This immune-inhibitory/monocyte-cytokine regulation annotation reflects the
      core CD33 function in restraining myeloid cell activation.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28325905
  qualifier: enables
  review:
    summary: 'C1q-CD33 interaction evidence is meaningful, but the generic protein binding
      term loses the specific inhibitory-receptor/C1q context.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding is not informative for CD33 when the evidence 
      supports more specific interactions such as SHP-1/SHP-2 phosphatase binding, 
      sialic-acid glycan binding, or C1q-associated inhibitory receptor crosslinking.
- term:
    id: GO:0019903
    label: protein phosphatase binding
  evidence_type: IPI
  original_reference_id: PMID:10887109
  qualifier: enables
  review:
    summary: 'Phosphorylated CD33 ITIM motifs recruit and activate SHP-1/SHP-2 protein tyrosine
      phosphatases, forming the core inhibitory signaling mechanism.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0035579
    label: specific granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: 'This intracellular or granule-membrane localization is compatible with CD33
      biosynthesis, trafficking, or myeloid granule context, but it is not the main functional
      site of full-length CD33M inhibitory signaling.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      reflects isoform-specific intracellular localization, receptor 
      biosynthesis/trafficking, or neutrophil granule context rather than the main 
      cell-surface inhibitory Siglec role.
- term:
    id: GO:0070821
    label: tertiary granule membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review:
    summary: 'This intracellular or granule-membrane localization is compatible with CD33
      biosynthesis, trafficking, or myeloid granule context, but it is not the main functional
      site of full-length CD33M inhibitory signaling.'
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because the annotation is supported or plausible but 
      reflects isoform-specific intracellular localization, receptor 
      biosynthesis/trafficking, or neutrophil granule context rather than the main 
      cell-surface inhibitory Siglec role.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685607
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798747
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6799350
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0009897
    label: external side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:20660734
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: NAS
  original_reference_id: PMID:10611343
  qualifier: involved_in
  review:
    summary: 'CD33 mediates sialic-acid-dependent cell-cell interactions, but the broad cell
      adhesion term should be replaced with the more specific cell-cell adhesion term already
      supported for CD33.'
    action: MODIFY
    reason: The sialoadhesin/Siglec evidence supports sialic-acid-dependent cell-cell 
      adhesion rather than a broad adhesion process.
    proposed_replacement_terms:
    - id: GO:0098609
      label: cell-cell adhesion
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:3139766
  qualifier: located_in
  review:
    summary: 'Full-length CD33M is a type I plasma membrane/external cell-surface receptor
      on myeloid cells.'
    action: ACCEPT
    reason: This location is consistent with full-length CD33M acting as a type I 
      cell-surface Siglec/inhibitory receptor on myeloid cells.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:10611343
  qualifier: involved_in
  review:
    summary: 'This broad signaling or proliferation annotation is supported by CD33 engagement
      experiments and fits the myeloid inhibitory receptor role.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0007267
    label: cell-cell signaling
  evidence_type: TAS
  original_reference_id: PMID:10611343
  qualifier: involved_in
  review:
    summary: 'This broad signaling or proliferation annotation is supported by CD33 engagement
      experiments and fits the myeloid inhibitory receptor role.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: TAS
  original_reference_id: PMID:10611343
  qualifier: involved_in
  review:
    summary: 'This broad signaling or proliferation annotation is supported by CD33 engagement
      experiments and fits the myeloid inhibitory receptor role.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
- term:
    id: GO:0038023
    label: signaling receptor activity
  evidence_type: TAS
  original_reference_id: PMID:10611343
  qualifier: enables
  review:
    summary: 'This broad signaling or proliferation annotation is supported by CD33 engagement
      experiments and fits the myeloid inhibitory receptor role.'
    action: ACCEPT
    reason: This term captures the core CD33/Siglec-3 role as a myeloid cell-surface 
      sialic-acid-binding inhibitory receptor that signals through phosphorylated ITIMs 
      and SHP-1/SHP-2 phosphatase recruitment.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location 
    vocabulary mapping, accompanied by conservative changes to GO terms applied by 
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:10206955
  title: The myeloid-specific sialic acid-binding receptor, CD33, associates with the 
    protein-tyrosine phosphatases, SHP-1 and SHP-2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached; supports tyrosine-phosphorylated CD33 recruitment of 
      SHP-1 and SHP-2.
- id: PMID:10556798
  title: The sialoadhesin CD33 is a myeloid-specific inhibitory receptor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached; supports CD33 as a myeloid inhibitory receptor that 
      recruits/activates SHP-1 and regulates Fc-gamma receptor signaling.
- id: PMID:10611343
  title: Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or 
    leukemic myeloid cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract cached; supports CD33 engagement inhibiting 
      proliferation/survival of myeloid cells.
- id: PMID:10887109
  title: Myeloid specific human CD33 is an inhibitory receptor with differential ITIM 
    function in recruiting the phosphatases SHP-1 and SHP-2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached; supports ITIM phosphorylation, SHP-1/SHP-2 
      recruitment, and inhibitory receptor function.
- id: PMID:15597323
  title: Constitutive repressor activity of CD33 on human monocytes requires sialic acid
    recognition and phosphoinositide 3-kinase-mediated intracellular signaling.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached; supports sialic-acid-dependent repression of monocyte
      activation and cytokine production.
- id: PMID:17947393
  title: 'ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain,
    tyrosine phosphorylation, and the tyrosine phosphatases, Shp1 and Shp2.'
  findings: []
- id: PMID:20660734
  title: MicroRNAs enriched in hematopoietic stem cells differentially regulate 
    long-term hematopoietic output.
  findings: []
- id: PMID:21278227
  title: Epitope mapping, expression and post-translational modifications of two 
    isoforms of CD33 (CD33M and CD33m) on lymphoid and myeloid human cells.
  findings: []
- id: PMID:24216507
  title: Induction of myelodysplasia by myeloid-derived suppressor cells.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:27044754
  title: FRMD4A-cytohesin signaling modulates the cellular release of tau.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Abstract-only cache does not verify the CD33-specific tau 
      secretion/protein secretion annotation.
- id: PMID:28325905
  title: Evidence for C1q-mediated crosslinking of CD33/LAIR-1 inhibitory 
    immunoreceptors and biological control of CD33/LAIR-1 expression.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text cached; supports C1q interaction/crosslinking of CD33/LAIR-1
      inhibitory receptors.
- id: PMID:28747436
  title: The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss 
    of function via diversion to an intracellular pool.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract cached; supports CD33m splice isoform diversion to 
      peroxisomes and Alzheimer-protective loss-of-function context.
- id: PMID:3139766
  title: Isolation of a cDNA encoding CD33, a differentiation antigen of myeloid 
    progenitor cells.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32822567
  title: A Human IgSF Cell-Surface Interactome Reveals a Complex Network of 
    Protein-Protein Interactions.
  findings: []
- id: PMID:7718872
  title: Characterization of CD33 as a new member of the sialoadhesin family of cellular
    interaction molecules.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract cached; direct evidence that CD33 is a sialic-acid-dependent 
      cell adhesion molecule.
- id: Reactome:R-HSA-5685607
  title: Sialic acid binds SIGLEC
  findings: []
- id: Reactome:R-HSA-6798747
  title: Exocytosis of tertiary granule membrane proteins
  findings: []
- id: Reactome:R-HSA-6799350
  title: Exocytosis of specific granule membrane proteins
  findings: []
- id: file:human/CD33/CD33-deep-research-falcon.md
  title: Falcon deep research report for CD33
  findings:
  - statement: Falcon corroborates the core CD33 model, framing it as a non-enzymatic
      sialic-acid-recognizing lectin receptor and adding microglial detail that CD33
      inhibitory signaling antagonizes the SYK/ERK activation axis.
    supporting_text: In microglia, deletion or functional disruption of CD33 leads
      to increased phosphorylation of spleen tyrosine kinase (SYK) and extracellular
      signal-regulated kinases 1 and 2 (ERK1/2), indicating relief from CD33-mediated
      inhibition
core_functions:
- molecular_function:
    id: GO:0033691
    label: sialic acid binding
  description: CD33 is a Siglec whose extracellular Ig-like domain recognizes sialylated
    glycans, supporting sialic-acid-dependent cell-cell interactions and 
    ligand-dependent control of myeloid inhibitory receptor activity.
  directly_involved_in:
  - id: GO:0098609
    label: cell-cell adhesion
  - id: GO:0002765
    label: immune response-inhibiting signal transduction
  - id: GO:0150102
    label: negative regulation of monocyte activation
  locations:
  - id: GO:0009897
    label: external side of plasma membrane
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:7718872
    supporting_text: CD33 can function as a sialic acid-dependent cell adhesion molecule
  - reference_id: PMID:15597323
    supporting_text: depending on the sialic acid microenvironment for its repressor
      activity
  - reference_id: file:human/CD33/CD33-deep-research-falcon.md
    supporting_text: CD33 functions as a lectin receptor that recognizes terminal
      sialic acids on cell-surface glycans rather than catalyzing enzymatic reactions
- molecular_function:
    id: GO:0019903
    label: protein phosphatase binding
  description: Upon receptor engagement, CD33 cytoplasmic ITIM tyrosines are 
    phosphorylated and recruit SHP-1/PTPN6 and SHP-2/PTPN11 phosphatases, enabling 
    inhibitory signaling that restrains myeloid activation, cytokine production, 
    Fc-gamma receptor calcium responses, and proliferation.
  directly_involved_in:
  - id: GO:0002765
    label: immune response-inhibiting signal transduction
  - id: GO:0038094
    label: Fc-gamma receptor signaling pathway
  - id: GO:0150102
    label: negative regulation of monocyte activation
  - id: GO:0032691
    label: negative regulation of interleukin-1 beta production
  - id: GO:0032717
    label: negative regulation of interleukin-8 production
  - id: GO:0032720
    label: negative regulation of tumor necrosis factor production
  locations:
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:10206955
    supporting_text: Phosphorylated CD33 recruited both the protein-tyrosine 
      phosphatases, SHP-1 and SHP-2
  - reference_id: PMID:10887109
    supporting_text: CD33 is an inhibitory receptor and also that SHP-1 phosphatase has 
      a significant role in mediating CD33 function
  - reference_id: PMID:10556798
    supporting_text: CD33 is an inhibitory receptor that may regulate FcgammaRI signal 
      transduction
proposed_new_terms: []
suggested_questions:
- question: Should CD33 C1q interaction be represented by a more specific binding term 
    than generic protein binding, and how should that relate to LAIR-1/CD33 inhibitory 
    receptor crosslinking?
  experts:
  - CD33/Siglec experts
  - GO immunoreceptor signaling curators
- question: Should CD33m peroxisome localization be curated as isoform-specific despite 
    GOA currently lacking an isoform qualifier?
  experts:
  - CD33 isoform experts
  - GO isoform annotation curators
- question: Can the CD33-specific result behind the tau/protein secretion screen
    annotation be verified from full text or supplementary data?
  experts:
  - Alzheimer tau secretion experts
  - GO evidence reviewers
- question: Does CD33 (SIGLEC3) inhibitory signaling antagonize the TREM2/DAP12-SYK-ERK
    activation axis in microglia, and should this be captured as negative regulation
    of microglial activation/phagocytosis? The AD-risk allele rs3865444 favors more
    full-length CD33M (more inhibition, reduced amyloid-beta phagocytosis) whereas
    the protective rs12459419 promotes the exon-2-skipped CD33m isoform, so isoform
    directionality may need to be reflected alongside any new microglial process term.
  experts:
  - CD33/Siglec experts
  - Alzheimer disease microglia experts
  - GO immunoreceptor signaling curators
suggested_experiments:
- description: Compare full-length CD33M, CD33m, ITIM tyrosine mutants, and 
    sialic-acid-binding mutants in primary human monocytes and iPSC-derived microglia 
    for surface localization, SHP-1/SHP-2 recruitment, cytokine output, phagocytosis, 
    and amyloid-beta uptake.
  hypothesis: CD33M suppresses myeloid/microglial activation through coupled sialic-acid
    recognition and ITIM/SHP signaling, whereas CD33m reduces this pathway primarily by 
    cell-surface loss of function.
  experiment_type: isoform and ITIM separation-of-function assay
- description: Test C1q binding to CD33M and CD33m with purified ectodomains and 
    monocyte/microglia surface assays, then measure whether C1q-dependent CD33/LAIR-1 
    crosslinking changes ITIM phosphorylation and inflammatory responses.
  hypothesis: C1q acts as a context-specific ligand/crosslinker for CD33 inhibitory 
    signaling rather than a generic protein-binding partner.
  experiment_type: ligand-binding and inhibitory signaling assay

CD33

Gene Description

Existing Annotations Review

Core Functions

CD33 is a Siglec whose extracellular Ig-like domain recognizes sialylated glycans, supporting sialic-acid-dependent cell-cell interactions and ligand-dependent control of myeloid inhibitory receptor activity.

Upon receptor engagement, CD33 cytoplasmic ITIM tyrosines are phosphorylated and recruit SHP-1/PTPN6 and SHP-2/PTPN11 phosphatases, enabling inhibitory signaling that restrains myeloid activation, cytokine production, Fc-gamma receptor calcium responses, and proliferation.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: CD33 (SIGLEC3) - Functional Annotation

Gene Identity Verification

Protein Structure and Domain Organization

Overall Architecture

Extracellular Domains

Transmembrane Domain

Cytoplasmic Domain

Primary Function: Sialic Acid Recognition

Substrate Specificity

Molecular Mechanism of Glycan Binding

Physiological Ligands

Cellular Localization and Expression

Subcellular Localization

Cellular Expression Pattern

Signaling Mechanisms and Biochemical Pathways

ITIM-Mediated Inhibitory Signaling

Recruitment of SHP-1 and SHP-2 Phosphatases

Antagonism of Activating Pathways

Biological Functions

Immune Regulation and Self-Recognition

Regulation of Phagocytosis

Control of Inflammatory Responses

Alternative Isoforms and Functional Consequences

CD33 Isoform Structure

Functional Differences Between Isoforms

Disease Relevance and Therapeutic Implications

Alzheimer's Disease

Acute Myeloid Leukemia

Viral Immune Evasion

Summary

Artifacts

Citations

📚 Additional Documentation

Notes

CD33 curation notes

2026-06-19

2026-06-20 Second-Pass Review Notes

Falcon deep research integration (2026-06-21)

📄 View Raw YAML