CD33

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.

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

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Notes

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