PIK3CD encodes p110delta, the leukocyte-enriched catalytic subunit of class IA phosphoinositide 3-kinase delta. In p85-family regulatory complexes, p110delta phosphorylates membrane phosphoinositides, especially PI(4,5)P2, to generate PIP3 downstream of immune receptors including BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40, Fc receptors, and cytokine/growth-factor receptors. The core curatable function is PIP3-producing lipid kinase activity in PI3K/AKT immune receptor signaling; broad immune phenotypes, chemotaxis, angiogenesis, and migration annotations are supported contextual outputs rather than the core molecular function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005737
cytoplasm
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0016477
cell migration
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Supported cell-migration role in specific leukocyte and glioma contexts, but non-core relative to lipid kinase signaling.
Reason: PIK3CD knockdown decreases glioma-cell migration and PI3Kdelta also affects leukocyte migration; these are downstream context-specific outputs rather than the core function.
Supporting Evidence:
PMID:22079609
Interestingly, knockdown of p110δ decreased the cell migration and invasion ability of all GBM cell lines tested.
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
|
|
GO:0005942
phosphatidylinositol 3-kinase complex
|
IBA
GO_REF:0000033 |
MODIFY |
Summary: The complex assignment is valid but should use the more specific class IA phosphatidylinositol 3-kinase complex term.
Reason: PIK3CD is not just any PI3K-complex component; it is the p110delta catalytic subunit of class IA p85-family regulatory complexes. GO:0005943 captures the correct complex subtype.
Proposed replacements:
phosphatidylinositol 3-kinase complex, class IA
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
|
|
GO:0043491
phosphatidylinositol 3-kinase/protein kinase B signal transduction
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated PIP3.
Reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This pathway term captures the central signaling output of PI3Kdelta even when the initiating receptor or cell type differs.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide 3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes downstream of receptor signaling in immune cells, particularly in lymphocytes.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
|
|
GO:0036092
phosphatidylinositol-3-phosphate biosynthetic process
|
IBA
GO_REF:0000033 |
MODIFY |
Summary: The PI3P biosynthetic-process term is too specific for a class III/VPS34-like product and is not the best process term for PIK3CD.
Reason: PIK3CD/p110delta primarily generates PIP3 from PI(4,5)P2 in class IA receptor signaling. A broader phosphatidylinositol phosphate biosynthetic process term better reflects the current GO vocabulary without implying class III PI3P-centered biology.
Proposed replacements:
phosphatidylinositol phosphate biosynthetic process
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
Reactome:R-HSA-389158
Upon binding to CD28, the PI3K enzyme catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
|
|
GO:0048015
phosphatidylinositol-mediated signaling
|
IBA
GO_REF:0000033 |
MODIFY |
Summary: The phosphatidylinositol-mediated signaling term is correct but too broad for PIK3CD.
Reason: PIK3CD is specifically a class IA PIP3-producing PI3K that feeds PI3K/AKT receptor signaling, so the more specific PI3K/AKT signal-transduction term is preferred.
Proposed replacements:
phosphatidylinositol 3-kinase/protein kinase B signal transduction
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide 3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes downstream of receptor signaling in immune cells, particularly in lymphocytes.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
|
|
GO:0005886
plasma membrane
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0016303
1-phosphatidylinositol-3-kinase activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic subunit.
Reason: This parent PI3K activity term is valid for p110delta, although GO:0046934 is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
Supporting Evidence:
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
|
|
GO:0035005
1-phosphatidylinositol-4-phosphate 3-kinase activity
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Supported phosphoinositide 3-kinase substrate activity, but PI4P phosphorylation is not the primary curatable core activity for PIK3CD.
Reason: Class I PI3Kdelta can act on phosphorylated phosphoinositides, and Reactome includes PIK3CD complexes in PI4P-to-PI(3,4)P2 reactions. The canonical core activity remains PI(4,5)P2-to-PIP3.
Supporting Evidence:
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
Reactome:R-HSA-1676109
These complexes along with phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunits alpha (PIK3C2A), beta (PIK3C2B), and gamma (PIK3C2G) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2).
|
|
GO:0000166
nucleotide binding
|
IEA
GO_REF:0000043 |
MODIFY |
Summary: The nucleotide-binding annotation is too generic for a lipid kinase and should be narrowed to ATP binding.
Reason: PIK3CD catalysis uses ATP; the broad nucleotide-binding term loses the catalytic context and is less informative than GO:0005524 ATP binding or the catalytic PI(4,5)P2 3-kinase MF.
Proposed replacements:
ATP binding
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
|
|
GO:0002250
adaptive immune response
|
IEA
GO_REF:0000043 |
KEEP AS NON CORE |
Summary: Supported adaptive-immune output, but this is a systems-level consequence of PI3Kdelta immune receptor signaling rather than the core molecular function.
Reason: Human disease genetics and leukocyte studies support a role in adaptive immunity, but the core function should remain PIP3-producing class IA PI3K signaling.
Supporting Evidence:
PMID:27616589
Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0002376
immune system process
|
IEA
GO_REF:0000043 |
MARK AS OVER ANNOTATED |
Summary: Correct directionally but too broad to be useful for PIK3CD curation.
Reason: PIK3CD has immune functions, but GO:0002376 is a very broad parent term. More informative annotations are BCR/TCR signaling, PI3K/AKT signaling, and specific leukocyte activation/migration processes.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0002443
leukocyte mediated immunity
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Supported leukocyte/immune response involvement, but non-core and broad relative to receptor-proximal PI3Kdelta signaling.
Reason: PIK3CD is leukocyte-enriched and affects immune responses, yet this broad immune-process term should not define the core function.
Supporting Evidence:
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
PMID:27616589
Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.
|
|
GO:0005524
ATP binding
|
IEA
GO_REF:0000043 |
KEEP AS NON CORE |
Summary: ATP binding is valid for the catalytic kinase domain, but it is generic relative to the core lipid kinase activity.
Reason: ATP is required for PI3Kdelta catalysis, yet ATP binding alone is not a specific description of the gene product function.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
|
|
GO:0005737
cytoplasm
|
IEA
GO_REF:0000044 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005829
cytosol
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005943
phosphatidylinositol 3-kinase complex, class IA
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: Correct class IA PI3K complex annotation for p110delta/p85-family regulatory assemblies.
Reason: This is the most specific existing CC term for PIK3CD complex membership and is supported by ComplexPortal entries and synthesis of the class IA p110delta-p85 regulatory complex.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
Reactome:R-HSA-2316434
In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD).
|
|
GO:0006629
lipid metabolic process
|
IEA
GO_REF:0000043 |
MODIFY |
Summary: The lipid metabolic process term is directionally correct but too broad for PIK3CD.
Reason: PIK3CD is specifically a phosphoinositide lipid kinase that produces 3-phosphoinositides/PIP3 in signaling contexts; phosphatidylinositol phosphate biosynthesis is the more informative same-aspect process replacement, while the specific PI(4,5)P2 3-kinase molecular function is handled separately.
Proposed replacements:
phosphatidylinositol phosphate biosynthetic process
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0006935
chemotaxis
|
IEA
GO_REF:0000043 |
MODIFY |
Summary: The generic chemotaxis annotation should be narrowed to the specific leukocyte chemotaxis processes supported for PIK3CD.
Reason: The evidence supports T-cell, B-cell, neutrophil, and mast-cell chemotaxis contexts rather than chemotaxis as a broad parent term.
Proposed replacements:
T cell chemotaxis
B cell chemotaxis
neutrophil chemotaxis
mast cell chemotaxis
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0006954
inflammatory response
|
IEA
GO_REF:0000043 |
KEEP AS NON CORE |
Summary: Supported inflammatory-response involvement, but it is a downstream physiological output of PI3Kdelta activity.
Reason: PI3Kdelta disruption alters inflammatory responses in vivo and PI3K lipid messengers control leukocyte signaling, but inflammation is a non-core phenotype/process relative to lipid kinase signaling.
Supporting Evidence:
PMID:17290298
Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0007166
cell surface receptor signaling pathway
|
IEA
GO_REF:0000117 |
MODIFY |
Summary: The broad cell-surface receptor signaling annotation should be narrowed to the immune receptor signaling pathways where PIK3CD has strong support.
Reason: PIK3CD acts downstream of immune receptors such as BCR, TCR, and CD28. Those terms are more informative and better supported than the generic cell-surface receptor signaling parent.
Proposed replacements:
B cell receptor signaling pathway
T cell receptor signaling pathway
T cell costimulation
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for B-cell receptor (BCR) signaling.
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for T-cell receptor (TCR) signaling.
|
|
GO:0010595
positive regulation of endothelial cell migration
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Supported endothelial/angiogenesis context, but non-core and tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
Reason: Cultured endothelial-cell work supports VEGF-induced Akt activation, proliferation, migration, tube formation, and retinal angiogenesis. This is a real contextual role, not the primary leukocyte-enriched core function.
Supporting Evidence:
PMID:31915155
Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
|
|
GO:0010628
positive regulation of gene expression
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: Over-annotation to positive regulation of gene expression. The available PIK3CD evidence supports upstream PI3K/AKT signaling more directly than this distal transcriptional-output term.
Reason: Gene-expression changes can occur downstream of PI3K/AKT/FOXO signaling, but the evidence supports this as a distal pathway output requiring careful attribution rather than a direct core PIK3CD function. This broad distal term should not be retained as a core annotation.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
It highlights pathway antagonism by PTEN/SHIP and connects FOXO-regulated transcription (e.g., immune differentiation programs) to PI3K signaling outputs (useful for downstream BP annotations, but requires careful evidence attribution if annotating those distal effects).
|
|
GO:0016301
kinase activity
|
IEA
GO_REF:0000120 |
MODIFY |
Summary: The generic enzyme-activity annotation is valid only as a distant parent and should be replaced by the specific lipid kinase activity.
Reason: PIK3CD is not merely a generic kinase/transferase; the evidence supports phosphoinositide 3-kinase activity, especially PI(4,5)P2 3-kinase activity.
Proposed replacements:
1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
|
|
GO:0016303
1-phosphatidylinositol-3-kinase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic subunit.
Reason: This parent PI3K activity term is valid for p110delta, although GO:0046934 is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
Supporting Evidence:
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
|
|
GO:0016740
transferase activity
|
IEA
GO_REF:0000043 |
MODIFY |
Summary: The generic enzyme-activity annotation is valid only as a distant parent and should be replaced by the specific lipid kinase activity.
Reason: PIK3CD is not merely a generic kinase/transferase; the evidence supports phosphoinositide 3-kinase activity, especially PI(4,5)P2 3-kinase activity.
Proposed replacements:
1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
|
|
GO:0022603
regulation of anatomical structure morphogenesis
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: Over-annotation to broad developmental, morphogenesis, or adhesion regulation terms.
Reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but these broad regulation terms over-generalize downstream effects and obscure the better-supported PI3Kdelta receptor-signaling biology.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0030154
cell differentiation
|
IEA
GO_REF:0000043 |
MODIFY |
Summary: The generic cell differentiation annotation should be narrowed to the specific leukocyte differentiation processes supported for PIK3CD.
Reason: The evidence supports B-cell, T-cell, NK-cell, and mast-cell differentiation contexts rather than undifferentiated cell differentiation as a generic parent.
Proposed replacements:
B cell differentiation
T cell differentiation
natural killer cell differentiation
mast cell differentiation
Supporting Evidence:
PMID:20200404
Thus, we provide novel evidence that p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.
PMID:17371229
In addition, p110delta regulates the differentiation of peripheral Th (helper T-cells) towards the Th1 and Th2 lineages.
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
|
|
GO:0030155
regulation of cell adhesion
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: Over-annotation to broad developmental, morphogenesis, or adhesion regulation terms.
Reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but these broad regulation terms over-generalize downstream effects and obscure the better-supported PI3Kdelta receptor-signaling biology.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0033031
positive regulation of neutrophil apoptotic process
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Supported neutrophil-death/apoptotic-process annotation, but non-core and context-dependent.
Reason: FcαRI-triggered neutrophil death requires class IA PI3K signaling in inflammatory contexts. This supports the annotation as a non-core immune effector process.
Supporting Evidence:
PMID:25339672
preactivation with cytokines or TLR agonists in vitro enhanced FcαRI-mediated death by additional recruitment of caspase-independent pathways, but this required PI3K class IA and MAPK signaling.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0042113
B cell activation
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Supported B-cell activation/function annotation, but downstream of the more core BCR signaling role.
Reason: PIK3CD is important for B-cell development and function. B-cell activation is real, but BCR signaling and PI3K/AKT signaling are the more precise core process annotations.
Supporting Evidence:
PMID:20200404
Thus, we provide novel evidence that p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for B-cell receptor (BCR) signaling.
|
|
GO:0043491
phosphatidylinositol 3-kinase/protein kinase B signal transduction
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated PIP3.
Reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This pathway term captures the central signaling output of PI3Kdelta even when the initiating receptor or cell type differs.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide 3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes downstream of receptor signaling in immune cells, particularly in lymphocytes.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
|
|
GO:0045087
innate immune response
|
IEA
GO_REF:0000120 |
KEEP AS NON CORE |
Summary: Supported innate-immune involvement, but this is a broad non-core immune-system output.
Reason: PI3Kdelta contributes to myeloid and innate leukocyte activities, but the precise core function is receptor-linked PIP3 production rather than innate immunity as a whole.
Supporting Evidence:
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
PMID:17290298
Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes.
|
|
GO:0046854
phosphatidylinositol phosphate biosynthetic process
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: Supported core process output of PI3Kdelta lipid kinase activity.
Reason: PIK3CD produces 3-phosphoinositides, especially PIP3, as the biochemical product of its class IA lipid kinase activity. This process term is broader than an ideal PIP3-biosynthesis term but is correct.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
Reactome:R-HSA-389158
Upon binding to CD28, the PI3K enzyme catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
|
|
GO:0046934
1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Core specific molecular function: p110delta phosphorylates PI(4,5)P2 to generate PIP3.
Reason: PI(4,5)P2 3-kinase activity is the specific catalytic activity that drives PI3Kdelta receptor signaling and PIP3-dependent AKT pathway recruitment.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
Reactome:R-HSA-389158
Upon binding to CD28, the PI3K enzyme catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
|
|
GO:0051094
positive regulation of developmental process
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: Over-annotation to broad developmental, morphogenesis, or adhesion regulation terms.
Reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but these broad regulation terms over-generalize downstream effects and obscure the better-supported PI3Kdelta receptor-signaling biology.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0051240
positive regulation of multicellular organismal process
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: Over-annotation to broad developmental, morphogenesis, or adhesion regulation terms.
Reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but these broad regulation terms over-generalize downstream effects and obscure the better-supported PI3Kdelta receptor-signaling biology.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:2000026
regulation of multicellular organismal development
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: Over-annotation to broad developmental, morphogenesis, or adhesion regulation terms.
Reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but these broad regulation terms over-generalize downstream effects and obscure the better-supported PI3Kdelta receptor-signaling biology.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0005515
protein binding
|
IPI
PMID:21827948 Dynamics of the phosphoinositide 3-kinase p110δ interaction ... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:22020336 p37δ is a new isoform of PI3K p110δ that increases cell prol... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:24165795 Dominant-activating germline mutations in the gene encoding ... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:28514442 Architecture of the human interactome defines protein commun... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:31031754 Case Study: Mechanism for Increased Follicular Helper T Cell... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005515
protein binding
|
IPI
PMID:40205054 Multimodal cell maps as a foundation for structural and func... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0005829
cytosol
|
IDA
GO_REF:0000052 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005515
protein binding
|
IPI
PMID:32606397 PI3K activation is enhanced by FOXM1D binding to p110 and p8... |
MARK AS OVER ANNOTATED |
Summary: Protein binding is an uninformative over-annotation for PIK3CD.
Reason: PIK3CD does interact with p85-family regulatory subunits and other signaling proteins, but GO:0005515 does not capture the meaningful function. The informative annotations are class IA PI3K complex membership and phosphoinositide kinase activity.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
|
|
GO:0031295
T cell costimulation
|
TAS
Reactome:R-HSA-389356 |
ACCEPT |
Summary: Supported CD28/T-cell costimulation context for PI3Kdelta signaling.
Reason: CD28 is a direct immune receptor context in which PI3K participates in costimulatory signaling and PIP3 generation. This is part of the core immune-receptor signaling frame for PIK3CD.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
Reactome:R-HSA-389356
The cytoplasmic tail of CD28, upon ligand binding, undergoes phosphorylation by Src family kinases like LCK and FYN, triggering downstream signaling pathways involving PI3K, VAV-1, Tec family kinases, AKT, and other adaptor proteins (Sharpe & Freeman 2002; Chen & Flies 2013).
Reactome:R-HSA-389158
Upon binding to CD28, the PI3K enzyme catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
|
|
GO:0046934
1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
|
TAS
Reactome:R-HSA-389158 |
ACCEPT |
Summary: Core specific molecular function: p110delta phosphorylates PI(4,5)P2 to generate PIP3.
Reason: PI(4,5)P2 3-kinase activity is the specific catalytic activity that drives PI3Kdelta receptor signaling and PIP3-dependent AKT pathway recruitment.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
Reactome:R-HSA-389158
Upon binding to CD28, the PI3K enzyme catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3).
|
|
GO:0006955
immune response
|
NAS
PMID:27616589 PI3Kδ and primary immunodeficiencies. |
KEEP AS NON CORE |
Summary: Supported leukocyte/immune response involvement, but non-core and broad relative to receptor-proximal PI3Kdelta signaling.
Reason: PIK3CD is leukocyte-enriched and affects immune responses, yet this broad immune-process term should not define the core function.
Supporting Evidence:
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
PMID:27616589
Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.
|
|
GO:0030183
B cell differentiation
|
NAS
PMID:20200404 The catalytic PI3K isoforms p110gamma and p110delta contribu... |
KEEP AS NON CORE |
Summary: Supported B-cell differentiation/development role, but non-core relative to PI3Kdelta catalytic signaling.
Reason: B-cell developmental phenotypes are well supported, but they are downstream organism/cell lineage consequences of PIP3-producing PI3Kdelta signaling.
Supporting Evidence:
PMID:20200404
Thus, we provide novel evidence that p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for B-cell receptor (BCR) signaling.
|
|
GO:0030217
T cell differentiation
|
NAS
PMID:17371229 The PI3K p110delta controls T-cell development, differentiat... |
KEEP AS NON CORE |
Summary: Supported T-cell differentiation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: T-cell differentiation is a supported immune-cell outcome of p110delta activity, not the core molecular function itself.
Supporting Evidence:
PMID:17371229
In addition, p110delta regulates the differentiation of peripheral Th (helper T-cells) towards the Th1 and Th2 lineages.
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
|
|
GO:0038084
vascular endothelial growth factor signaling pathway
|
IGI
PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogen... |
KEEP AS NON CORE |
Summary: Supported endothelial/angiogenesis context, but non-core and tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
Reason: Cultured endothelial-cell work supports VEGF-induced Akt activation, proliferation, migration, tube formation, and retinal angiogenesis. This is a real contextual role, not the primary leukocyte-enriched core function.
Supporting Evidence:
PMID:31915155
Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
|
|
GO:0010595
positive regulation of endothelial cell migration
|
IGI
PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogen... |
KEEP AS NON CORE |
Summary: Supported endothelial/angiogenesis context, but non-core and tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
Reason: Cultured endothelial-cell work supports VEGF-induced Akt activation, proliferation, migration, tube formation, and retinal angiogenesis. This is a real contextual role, not the primary leukocyte-enriched core function.
Supporting Evidence:
PMID:31915155
Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
|
|
GO:0001938
positive regulation of endothelial cell proliferation
|
IGI
PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogen... |
KEEP AS NON CORE |
Summary: Supported endothelial/angiogenesis context, but non-core and tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
Reason: Cultured endothelial-cell work supports VEGF-induced Akt activation, proliferation, migration, tube formation, and retinal angiogenesis. This is a real contextual role, not the primary leukocyte-enriched core function.
Supporting Evidence:
PMID:31915155
Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
|
|
GO:0043491
phosphatidylinositol 3-kinase/protein kinase B signal transduction
|
IGI
PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogen... |
ACCEPT |
Summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated PIP3.
Reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This pathway term captures the central signaling output of PI3Kdelta even when the initiating receptor or cell type differs.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide 3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes downstream of receptor signaling in immune cells, particularly in lymphocytes.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
|
|
GO:0045766
positive regulation of angiogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Supported endothelial/angiogenesis context, but non-core and tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
Reason: Cultured endothelial-cell work supports VEGF-induced Akt activation, proliferation, migration, tube formation, and retinal angiogenesis. This is a real contextual role, not the primary leukocyte-enriched core function.
Supporting Evidence:
PMID:31915155
Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
|
|
GO:1905278
positive regulation of epithelial tube formation
|
IGI
PMID:31915155 PI3Kδ as a Novel Therapeutic Target in Pathological Angiogen... |
KEEP AS NON CORE |
Summary: Supported endothelial/angiogenesis context, but non-core and tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
Reason: Cultured endothelial-cell work supports VEGF-induced Akt activation, proliferation, migration, tube formation, and retinal angiogenesis. This is a real contextual role, not the primary leukocyte-enriched core function.
Supporting Evidence:
PMID:31915155
Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
|
|
GO:0033031
positive regulation of neutrophil apoptotic process
|
IMP
PMID:25339672 Human IgA Fc receptor FcαRI (CD89) triggers different forms ... |
KEEP AS NON CORE |
Summary: Supported neutrophil-death/apoptotic-process annotation, but non-core and context-dependent.
Reason: FcαRI-triggered neutrophil death requires class IA PI3K signaling in inflammatory contexts. This supports the annotation as a non-core immune effector process.
Supporting Evidence:
PMID:25339672
preactivation with cytokines or TLR agonists in vitro enhanced FcαRI-mediated death by additional recruitment of caspase-independent pathways, but this required PI3K class IA and MAPK signaling.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0043491
phosphatidylinositol 3-kinase/protein kinase B signal transduction
|
IMP
PMID:25339672 Human IgA Fc receptor FcαRI (CD89) triggers different forms ... |
ACCEPT |
Summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated PIP3.
Reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This pathway term captures the central signaling output of PI3Kdelta even when the initiating receptor or cell type differs.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide 3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes downstream of receptor signaling in immune cells, particularly in lymphocytes.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
|
|
GO:0001779
natural killer cell differentiation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported NK-cell differentiation role, but non-core relative to PI3Kdelta catalytic signaling.
Reason: PI3Kdelta participates in NK-cell development and migration, but this is a leukocyte-specific cellular outcome rather than the core lipid kinase function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
|
|
GO:0001819
positive regulation of cytokine production
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported cytokine-production role, but non-core and downstream of immune receptor signaling.
Reason: Cytokine-production changes are leukocyte outputs of PI3Kdelta signaling, not the primary biochemical function.
Supporting Evidence:
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for T-cell receptor (TCR) signaling.
|
|
GO:0002250
adaptive immune response
|
TAS
PMID:17290298 PI3K delta and PI3K gamma: partners in crime in inflammation... |
KEEP AS NON CORE |
Summary: Supported adaptive-immune output, but this is a systems-level consequence of PI3Kdelta immune receptor signaling rather than the core molecular function.
Reason: Human disease genetics and leukocyte studies support a role in adaptive immunity, but the core function should remain PIP3-producing class IA PI3K signaling.
Supporting Evidence:
PMID:27616589
Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0002551
mast cell chemotaxis
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: PI3Kdelta affects migration of multiple leukocyte types, but these are cell-type-specific outputs of the core PIP3-generating immune signaling function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0002679
respiratory burst involved in defense response
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported neutrophil respiratory-burst role, but non-core relative to the catalytic PI3Kdelta signaling function.
Reason: PI3Kdelta contributes to neutrophil respiratory burst as a myeloid effector output, but this is not the core molecular function.
Supporting Evidence:
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0006954
inflammatory response
|
TAS
PMID:17290298 PI3K delta and PI3K gamma: partners in crime in inflammation... |
KEEP AS NON CORE |
Summary: Supported inflammatory-response involvement, but it is a downstream physiological output of PI3Kdelta activity.
Reason: PI3Kdelta disruption alters inflammatory responses in vivo and PI3K lipid messengers control leukocyte signaling, but inflammation is a non-core phenotype/process relative to lipid kinase signaling.
Supporting Evidence:
PMID:17290298
Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0006954
inflammatory response
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported inflammatory-response involvement, but it is a downstream physiological output of PI3Kdelta activity.
Reason: PI3Kdelta disruption alters inflammatory responses in vivo and PI3K lipid messengers control leukocyte signaling, but inflammation is a non-core phenotype/process relative to lipid kinase signaling.
Supporting Evidence:
PMID:17290298
Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes.
PMID:20940048
As a result of the broad effects of PI3Kδ in leukocyte functions, the disruption of PI3Kδ expression or activity leads to decreased inflammatory and immune responses in vivo.
|
|
GO:0010818
T cell chemotaxis
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: PI3Kdelta affects migration of multiple leukocyte types, but these are cell-type-specific outputs of the core PIP3-generating immune signaling function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0016303
1-phosphatidylinositol-3-kinase activity
|
TAS
PMID:17290298 PI3K delta and PI3K gamma: partners in crime in inflammation... |
ACCEPT |
Summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic subunit.
Reason: This parent PI3K activity term is valid for p110delta, although GO:0046934 is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
Supporting Evidence:
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
|
|
GO:0030101
natural killer cell activation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported NK-cell activation context, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: NK-cell activation is a supported immune output; the central curatable function remains PI3Kdelta PIP3 production in leukocyte signaling.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
|
|
GO:0030217
T cell differentiation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported T-cell differentiation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: T-cell differentiation is a supported immune-cell outcome of p110delta activity, not the core molecular function itself.
Supporting Evidence:
PMID:17371229
In addition, p110delta regulates the differentiation of peripheral Th (helper T-cells) towards the Th1 and Th2 lineages.
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
|
|
GO:0030593
neutrophil chemotaxis
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: PI3Kdelta affects migration of multiple leukocyte types, but these are cell-type-specific outputs of the core PIP3-generating immune signaling function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0035747
natural killer cell chemotaxis
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: PI3Kdelta affects migration of multiple leukocyte types, but these are cell-type-specific outputs of the core PIP3-generating immune signaling function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0035754
B cell chemotaxis
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: PI3Kdelta affects migration of multiple leukocyte types, but these are cell-type-specific outputs of the core PIP3-generating immune signaling function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0042110
T cell activation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported T-cell activation/function annotation, but downstream of the more core TCR/CD28 signaling role.
Reason: PIK3CD contributes to T-cell development, activation, and migration. The T-cell activation process is supported but is a cellular outcome of the core TCR/CD28 PI3K signaling function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for T-cell receptor (TCR) signaling.
|
|
GO:0042113
B cell activation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported B-cell activation/function annotation, but downstream of the more core BCR signaling role.
Reason: PIK3CD is important for B-cell development and function. B-cell activation is real, but BCR signaling and PI3K/AKT signaling are the more precise core process annotations.
Supporting Evidence:
PMID:20200404
Thus, we provide novel evidence that p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for B-cell receptor (BCR) signaling.
|
|
GO:0043303
mast cell degranulation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported mast-cell degranulation role, but non-core relative to the catalytic PI3Kdelta function.
Reason: PI3Kdelta contributes to mast-cell degranulation, but this is a cell-type-specific effector output rather than the core molecular function.
Supporting Evidence:
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0043491
phosphatidylinositol 3-kinase/protein kinase B signal transduction
|
TAS
PMID:17290298 PI3K delta and PI3K gamma: partners in crime in inflammation... |
ACCEPT |
Summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated PIP3.
Reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This pathway term captures the central signaling output of PI3Kdelta even when the initiating receptor or cell type differs.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide 3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes downstream of receptor signaling in immune cells, particularly in lymphocytes.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20940048
PI3Kδ is a lipid kinase of the PI3K class IA family involved in early signaling events of leukocytes responding to a wide variety of stimuli.
|
|
GO:0045087
innate immune response
|
TAS
PMID:17290298 PI3K delta and PI3K gamma: partners in crime in inflammation... |
KEEP AS NON CORE |
Summary: Supported innate-immune involvement, but this is a broad non-core immune-system output.
Reason: PI3Kdelta contributes to myeloid and innate leukocyte activities, but the precise core function is receptor-linked PIP3 production rather than innate immunity as a whole.
Supporting Evidence:
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
PMID:17290298
Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes.
|
|
GO:0045087
innate immune response
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported innate-immune involvement, but this is a broad non-core immune-system output.
Reason: PI3Kdelta contributes to myeloid and innate leukocyte activities, but the precise core function is receptor-linked PIP3 production rather than innate immunity as a whole.
Supporting Evidence:
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
PMID:17290298
Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second messengers that control an array of intracellular signalling pathways that are known to have important roles in leukocytes.
|
|
GO:0050852
T cell receptor signaling pathway
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
ACCEPT |
Summary: Supported TCR signaling role for PI3Kdelta.
Reason: UniProt and the literature synthesis identify p110delta as required for TCR signaling, making this one of the core immune receptor signaling processes for PIK3CD.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for T-cell receptor (TCR) signaling.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
|
|
GO:0050853
B cell receptor signaling pathway
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
ACCEPT |
Summary: Supported BCR signaling role for PI3Kdelta.
Reason: p110delta is required for BCR signaling and B-cell functional outputs; this is one of the strongest process annotations for PIK3CD.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
Required for B-cell receptor (BCR) signaling.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
PMID:20200404
Thus, we provide novel evidence that p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.
|
|
GO:0060374
mast cell differentiation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported mast-cell differentiation role, but non-core relative to the catalytic PI3Kdelta function.
Reason: Mast-cell maturation/differentiation is a supported leukocyte-cell output of PI3Kdelta signaling, not the core molecular activity.
Supporting Evidence:
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0072672
neutrophil extravasation
|
TAS
PMID:20940048 Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signali... |
KEEP AS NON CORE |
Summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core relative to receptor-proximal PI3Kdelta signaling.
Reason: PI3Kdelta affects migration of multiple leukocyte types, but these are cell-type-specific outputs of the core PIP3-generating immune signaling function.
Supporting Evidence:
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
PMID:20940048
The role of PI3Kδ in myeloid cell activities, such as inflammation driven cell infiltration, neutrophil oxidative burst, immune complex mediated macrophage activation, as well as mast cell maturation and degranulation, has been well illustrated in various studies.
|
|
GO:0010628
positive regulation of gene expression
|
IMP
PMID:22079609 The catalytic phosphoinositol 3-kinase isoform p110δ is requ... |
MARK AS OVER ANNOTATED |
Summary: Over-annotation to positive regulation of gene expression. The available PIK3CD evidence supports upstream PI3K/AKT signaling more directly than this distal transcriptional-output term.
Reason: Gene-expression changes can occur downstream of PI3K/AKT/FOXO signaling, but the evidence supports this as a distal pathway output requiring careful attribution rather than a direct core PIK3CD function. This broad distal term should not be retained as a core annotation.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Many downstream readouts (e.g., pAKT, pS6) are not isoform-specific, and class I PI3Ks share overlapping functions; p110δ is leukocyte-enriched but not exclusively expressed, so immune-context evidence is strongest for PIK3CD-specific BP claims.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
It highlights pathway antagonism by PTEN/SHIP and connects FOXO-regulated transcription (e.g., immune differentiation programs) to PI3K signaling outputs (useful for downstream BP annotations, but requires careful evidence attribution if annotating those distal effects).
|
|
GO:0030335
positive regulation of cell migration
|
IMP
PMID:22079609 The catalytic phosphoinositol 3-kinase isoform p110δ is requ... |
KEEP AS NON CORE |
Summary: Supported cell-migration role in specific leukocyte and glioma contexts, but non-core relative to lipid kinase signaling.
Reason: PIK3CD knockdown decreases glioma-cell migration and PI3Kdelta also affects leukocyte migration; these are downstream context-specific outputs rather than the core function.
Supporting Evidence:
PMID:22079609
Interestingly, knockdown of p110δ decreased the cell migration and invasion ability of all GBM cell lines tested.
PMID:20940048
PI3Kδ participates in the development, activation and migration of T cells and NK cells.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1676048 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-1676109 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9012657 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9021627 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9027275 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005829
cytosol
|
TAS
Reactome:R-HSA-9606887 |
KEEP AS NON CORE |
Summary: Supported cytoplasmic or cytosolic localization, but this is the resting/general pool rather than the most informative activated signaling site.
Reason: UniProt records cytoplasmic localization and the deep research report describes resting p110delta-p85 complexes as cytosolic. The functionally decisive event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be treated as the core location.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-2045911 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-2076220 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-2316434 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-2400009 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-388830 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-388832 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-389158 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-508247 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-879917 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-8854905 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-912627 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-914182 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005886
plasma membrane
|
TAS
Reactome:R-HSA-9606887 |
ACCEPT |
Summary: Supported core activated-site localization. PI3Kdelta is recruited to plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates reside.
Reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2 substrate is membrane localized and receptor phosphotyrosine signals recruit the p85-p110delta complex to the plasma membrane.
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside.
Reactome:R-HSA-1676048
At the plasma membrane, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits form complexes with regulatory subunits.
|
|
GO:0005942
phosphatidylinositol 3-kinase complex
|
NAS
PMID:9113989 P110delta, a novel phosphoinositide 3-kinase in leukocytes. |
MODIFY |
Summary: The complex assignment is valid but should use the more specific class IA phosphatidylinositol 3-kinase complex term.
Reason: PIK3CD is not just any PI3K-complex component; it is the p110delta catalytic subunit of class IA p85-family regulatory complexes. GO:0005943 captures the correct complex subtype.
Proposed replacements:
phosphatidylinositol 3-kinase complex, class IA
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
|
|
GO:0005942
phosphatidylinositol 3-kinase complex
|
NAS
PMID:9235916 p110delta, a novel phosphatidylinositol 3-kinase catalytic s... |
MODIFY |
Summary: The complex assignment is valid but should use the more specific class IA phosphatidylinositol 3-kinase complex term.
Reason: PIK3CD is not just any PI3K-complex component; it is the p110delta catalytic subunit of class IA p85-family regulatory complexes. GO:0005943 captures the correct complex subtype.
Proposed replacements:
phosphatidylinositol 3-kinase complex, class IA
Supporting Evidence:
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells.
file:human/PIK3CD/PIK3CD-uniprot.txt
ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex class IA, p110delta/p85alpha.
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
|
|
GO:0006468
protein phosphorylation
|
NAS
PMID:9113989 P110delta, a novel phosphoinositide 3-kinase in leukocytes. |
MODIFY |
Summary: Over-annotation to protein phosphorylation. PIK3CD is primarily a phosphoinositide lipid kinase, not a protein kinase.
Reason: PMID:9113989 reports lipid substrate specificity and explicitly distinguishes p110delta from p110alpha by noting that it does not phosphorylate p85, despite intrinsic autophosphorylation. The same-aspect replacement should be lipid phosphorylation rather than general protein phosphorylation; the specific PI(4,5)P2 3-kinase molecular function is handled separately.
Proposed replacements:
lipid phosphorylation
Supporting Evidence:
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
PMID:9113989
Unlike p110alpha, p110delta does not phosphorylate p85 but instead harbors an intrinsic autophosphorylation capacity.
|
|
GO:0007165
signal transduction
|
NAS
PMID:9113989 P110delta, a novel phosphoinositide 3-kinase in leukocytes. |
MODIFY |
Summary: The generic signal-transduction annotation should be narrowed to PI3K/AKT and immune receptor signaling.
Reason: PIK3CD participates in signaling by generating PIP3 downstream of receptor activation. The generic signal transduction parent obscures the specific PI3K/AKT, BCR, and TCR pathways supported by the evidence.
Proposed replacements:
phosphatidylinositol 3-kinase/protein kinase B signal transduction
B cell receptor signaling pathway
T cell receptor signaling pathway
Supporting Evidence:
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD.
|
|
GO:0016303
1-phosphatidylinositol-3-kinase activity
|
NAS
PMID:9235916 p110delta, a novel phosphatidylinositol 3-kinase catalytic s... |
ACCEPT |
Summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic subunit.
Reason: This parent PI3K activity term is valid for p110delta, although GO:0046934 is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
Supporting Evidence:
PMID:9235916
Recombinant p110delta phosphorylates phosphatidylinositol and coimmunoprecipitates with p85.
PMID:9113989
p110delta displays a broad phosphoinositide lipid substrate specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins and with GTP-bound Ras.
file:human/PIK3CD/PIK3CD-deep-research-falcon.md
Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
|
Q: Which PIK3CD-dependent leukocyte migration, neutrophil death, and endothelial angiogenesis annotations remain physiologically relevant in human primary cells after controlling for class I PI3K isoform redundancy and inhibitor selectivity?
Q: Should GO include a more specific biological-process term for class I PI3K-mediated PI(3,4,5)P3 biosynthesis to avoid using PI3P-centered or overly broad phosphatidylinositol phosphate biosynthetic process terms for PIK3CD?
Experiment: Use isoform-selective genetic rescue in human primary B and T cells to separate PIK3CD-specific BCR, TCR, and CD28 signaling outputs from overlapping PIK3CA/PIK3CB/PIK3CG class I PI3K activity.
Type: primary-cell genetic rescue and phosphoprotein/PIP3 readout
Experiment: Measure PI(4,5)P2-to-PIP3 and PI4P-to-PI(3,4)P2 product formation for p110delta-p85 complexes under matched in vitro and membrane-recruitment conditions to clarify whether PI4P kinase annotations should remain non-core.
Type: lipid kinase substrate-specificity assay
PIK3CD encodes the catalytic subunit p110δ of class IA phosphoinositide 3-kinase (PI3Kδ), a lipid kinase that produces PI(3,4,5)P3 (PIP3) at membranes downstream of receptor signaling in immune cells, particularly in lymphocytes. p110δ acts as a heterodimer with p85-family regulatory subunits, and receptor-triggered recruitment/relief of p85 inhibition is central to its regulated activity. (ijspeert2024hyperactivationofthe pages 2-4, ijspeert2024hyperactivationofthe pages 1-2)
Canonical record for protein identity: UniProt O00329 (https://www.uniprot.org/uniprotkb/O00329/). (No UniProt text was retrieved via tools; URL provided for curator convenience.)
Core enzymatic activity (lipid phosphorylation at D3 position): Class I PI3Ks phosphorylate membrane inositol phospholipids at the 3′ position; class IA enzymes (including p110δ) act on PI(4,5)P2 to generate PIP3, which serves as a membrane docking lipid for downstream signaling proteins. (ijspeert2024hyperactivationofthe pages 1-2, stokoe2005thephosphoinositide3kinase pages 1-3)
ATP dependence / catalytic-site context: PI3Kδ catalysis requires ATP; this is strongly supported indirectly by inhibitor mechanism studies contrasting ATP-competitive inhibitors (idelalisib) with non–ATP-competitive allosteric PI3Kδ inhibition (IOA-244), which alters enzyme kinetics consistent with catalytic-site ATP usage in the reaction. (johnson2023ioa244isa pages 6-7)
Class IA PI3K complex membership: Class IA PI3Ks function as heterodimers of p110 catalytic subunits and p85-family regulatory subunits; p85 stabilizes and inhibits p110 in resting state. (ijspeert2024hyperactivationofthe pages 2-4, stokoe2005thephosphoinositide3kinase pages 1-3)
Membrane recruitment as a key localization event: Upon receptor activation, p85 SH2 domains bind phosphotyrosine motifs (e.g., YxxM-containing motifs) on receptors/adaptors, recruiting the p85–p110δ complex to the plasma membrane, where phosphoinositide substrates reside and catalytic activity increases. (ijspeert2024hyperactivationofthe pages 2-4, stokoe2005thephosphoinositide3kinase pages 1-3)
PI3K→AKT→mTOR/FOXO axis: PIP3 recruits AKT to the plasma membrane for phosphorylation (PDK1/mTORC2 context) and downstream regulation of mTORC1/S6 and FOXO transcription factor localization/function. (ijspeert2024hyperactivationofthe pages 2-4, ijspeert2024hyperactivationofthe pages 1-2)
Immune receptor signaling context: In immune cells, class IA PI3K (including p110δ) propagates signaling downstream of BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40 (and related receptor/adaptor systems), framing the major immune-cell BP terms relevant for PIK3CD. (ijspeert2024hyperactivationofthe pages 2-4)
A foundational genetic study using p110δ-deficient mice demonstrates that p110δ is essential and nonredundant for effective BCR signaling.
Key experimental findings (Mol Cell Biol, 2002-12; DOI:10.1128/MCB.22.24.8580-8591.2002; URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002):
- Anti-IgM–induced intracellular Ca2+ mobilization in p110δ−/− B cells was reduced to ~25% of wild type, while ionomycin response was preserved, indicating a BCR-proximal signaling defect requiring p110δ. (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole media 9f8002cf)
- Proximal BCR signaling events (e.g., Btk and PLCγ2 tyrosine phosphorylation) occurred comparably, consistent with p110δ acting in the pathway needed for full Ca2+ signaling output. (jou2002essentialnonredundantrole pages 4-8)
GO interpretation: supports BP annotations for B cell receptor signaling pathway and intracellular calcium ion mobilization in B cells, with p110δ as a positive regulator/essential component in this context. (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole media 9f8002cf)
In the same p110δ knockout model:
- B cell developmental and compartment defects include reduced mature peripheral B cells and loss of B1 cells. (jou2002essentialnonredundantrole pages 1-2, jou2002essentialnonredundantrole pages 2-4)
- In vitro proliferation: p110δ−/− B cells showed decreased proliferation to anti-CD40 and LPS, and impaired responses to BCR crosslinking; bypass stimulation (PMA+ionomycin) was relatively preserved. (jou2002essentialnonredundantrole pages 4-8)
- Humoral immunity in vivo: reduced baseline serum immunoglobulins and impaired antigen-specific antibody responses—T-independent responses reduced and T-dependent antibody responses absent; germinal center formation impaired/absent by splenic staining after immunization. (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole media 9f8002cf)
Visual evidence from the primary paper (used here as supporting data displays): ELISA immunoglobulin panels, antigen-response panels, absent germinal center staining, and Ca2+ flux traces in wild-type vs p110δ−/− are captured in the retrieved figure crops. (jou2002essentialnonredundantrole media 9f8002cf, jou2002essentialnonredundantrole media 37876baa, jou2002essentialnonredundantrole media 7d2b61ed, jou2002essentialnonredundantrole media 3b78ec57)
GO interpretation: supports BP annotations such as B cell development, B cell activation, B cell proliferation, germinal center formation, and T-dependent humoral immune response. (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole pages 1-2, jou2002essentialnonredundantrole media 9f8002cf)
A 2024 conditional mouse model interrogated activated PI3Kδ signaling specifically within Foxp3+ Tregs, clarifying how PI3Kδ activity thresholds control tolerance.
Key recent study (J Immunol, 2024-06; DOI:10.4049/jimmunol.2400032; URL: https://doi.org/10.4049/jimmunol.2400032):
- Treg-restricted activated PI3Kδ (aPIK3CD) increased thymic Treg precursors and peripheral Treg numbers, yet Tregs displayed altered phenotype (e.g., increased PD-1) and reduced competitive fitness. (singh2024activatedpi3kδspecifically pages 1-3)
- Despite increased Treg counts, mice developed chronic inflammation, increased memory/effector CD4+/CD8+ T cells and enhanced IFN-γ secretion, plus spontaneous germinal center responses and broad autoantibody production. (singh2024activatedpi3kδspecifically pages 3-4, singh2024activatedpi3kδspecifically pages 1-3)
- Mechanistic linkage is consistent with PI3K→AKT→FOXO regulation (AKT phosphorylation, FOXO1 nuclear exclusion) affecting Treg stability/function. (singh2024activatedpi3kδspecifically pages 11-13)
GO interpretation: supports BP terms around regulatory T cell homeostasis, immune tolerance/negative regulation of immune response, and regulation of germinal center response/humoral immunity, with an explicit caveat that both loss and gain of PI3Kδ signaling can disrupt tolerance (directionality depends on activity threshold/context). (singh2024activatedpi3kδspecifically pages 1-3, singh2024activatedpi3kδspecifically pages 10-11)
A 2024 review synthesizes receptor contexts and regulatory mechanisms relevant to GO process selection:
- Class IA PI3K (p85–p110δ) is recruited downstream of immune receptors including BCR/TCR/CD28/ICOS/CD19/BAFF-R/CD40, producing PIP3 that drives AKT/mTOR/FOXO-linked programs. (ijspeert2024hyperactivationofthe pages 2-4, ijspeert2024hyperactivationofthe pages 1-2)
- It highlights pathway antagonism by PTEN/SHIP and connects FOXO-regulated transcription (e.g., immune differentiation programs) to PI3K signaling outputs (useful for downstream BP annotations, but requires careful evidence attribution if annotating those distal effects). (ijspeert2024hyperactivationofthe pages 2-4)
Source (Immunotherapy Advances, 2024-11; DOI:10.1093/immadv/ltae009; URL: https://doi.org/10.1093/immadv/ltae009) (ijspeert2024hyperactivationofthe pages 2-4, ijspeert2024hyperactivationofthe pages 1-2)
Because PI3Kδ is frequently perturbed pharmacologically (both experimentally and clinically), inhibitor properties are directly relevant to interpreting evidence used for GO assertions.
Allosteric vs ATP-competitive PI3Kδ inhibition (2023):
- IOA-244 (roginolisib) behaves as a non–ATP-competitive PI3Kδ inhibitor; kinetic data show minimal ATP Km shift but a strong Vmax reduction in a PIP3 production assay; biochemical IC50 ~19 nM and whole blood IC50 0.28 μM were reported (plus extensive selectivity profiling). (johnson2023ioa244isa pages 6-7, johnson2023ioa244isa pages 13-14)
- Idelalisib shows ATP-competitive behavior (Km shift) and strong PI3Kδ potency (KiNativ PI3Kδ IC50 1.3 nM), but with additional off-target activity and an active metabolite (GS-563117) with its own target spectrum, supporting strong GO curation caveats for pharmacology-derived functional claims. (johnson2023ioa244isa pages 6-7, johnson2023ioa244isa pages 13-14)
Source (Cancer Research Communications, 2023-04; DOI:10.1158/2767-9764.CRC-22-0477; URL: https://doi.org/10.1158/2767-9764.crc-22-0477) (johnson2023ioa244isa pages 6-7, johnson2023ioa244isa pages 13-14)
Leniolisib potency and isoform selectivity (2024):
- Leniolisib is reported as PI3Kδ-selective with IC50 11 nM (PI3Kδ) vs 244 nM (α), 424 nM (β), 2230 nM (γ). (de2024leniolisibanovel pages 1-2, cant2024pi3kδpathwaydysregulation pages 19-20)
Sources: Frontiers in Pharmacology (2024-02; DOI:10.3389/fphar.2024.1337436; URL: https://doi.org/10.3389/fphar.2024.1337436) (de2024leniolisibanovel pages 1-2) and JACI-In Practice (2024-01; DOI:10.1016/j.jaip.2023.09.016; URL: https://doi.org/10.1016/j.jaip.2023.09.016) (cant2024pi3kδpathwaydysregulation pages 19-20)
GO curation implication: inhibitor-based inference is useful for pathway placement (PI3Kδ dependence), but should be down-weighted unless selectivity, concentrations, and metabolites are controlled and accompanied by genetic corroboration. (johnson2023ioa244isa pages 6-7, cant2024pi3kδpathwaydysregulation pages 13-14)
Caveat for CC annotation: Much localization evidence in the retrieved sources is mechanistic/consensus (review synthesis). For strict experimental CC evidence codes, curators may prefer direct imaging/biochemical fractionation papers (not retrieved here in full). (ijspeert2024hyperactivationofthe pages 2-4, stokoe2005thephosphoinositide3kinase pages 1-3)
Disease genetics mainly reinforce dosage/threshold sensitivity of PI3Kδ signaling in immune function. For example, the Treg-conditional activation study demonstrates that hyperactive PI3Kδ signaling can paradoxically increase Treg numbers while impairing tolerance, emphasizing that GO BP annotations should avoid implying monotonic positive regulation for all downstream immune outcomes. (singh2024activatedpi3kδspecifically pages 1-3)
APDS-focused reviews (2024) frame PI3Kδ hyperactivation as driving excessive AKT/mTOR pathway activity in immune cells and motivating use of selective inhibitors; this is functionally relevant as it highlights pathway readouts (pAKT/pS6) used experimentally. (cant2024pi3kδpathwaydysregulation pages 1-3)
The following table compiles recommended MF/BP/CC terms with evidence summaries and traceable citations.
| GO aspect | Recommended GO term name | Evidence summary (1 line) | Key experimental system | Best supporting citation IDs |
|---|---|---|---|---|
| MF | phosphatidylinositol-4,5-bisphosphate 3-kinase activity | Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD. | Cell-free / review synthesis | (ijspeert2024hyperactivationofthe pages 1-2, stokoe2005thephosphoinositide3kinase pages 1-3) |
| MF | ATP binding | PI3Kδ catalytic activity is ATP-dependent; inhibitor kinetic studies distinguish ATP-competitive idelalisib from non-ATP-competitive IOA-244, reinforcing ATP use at the catalytic site. | Cell-free biochemical assays | (johnson2023ioa244isa pages 6-7, cant2024pi3kδpathwaydysregulation pages 19-20) |
| CC | class IA phosphatidylinositol 3-kinase complex | p110δ forms a class IA heterodimer with p85-family regulatory subunits, with p85 both stabilizing and inhibiting the catalytic subunit in resting cells. | Human / review synthesis | (ijspeert2024hyperactivationofthe pages 2-4, stokoe2005thephosphoinositide3kinase pages 1-3, berglund2024modulatingthepi3k pages 8-8) |
| CC | plasma membrane recruitment | Upon receptor phosphotyrosine signaling, SH2-containing p85 recruits the p85-p110δ complex to the plasma membrane where phosphoinositide substrates reside. | Human / review synthesis | (ijspeert2024hyperactivationofthe pages 2-4, ijspeert2024hyperactivationofthe pages 1-2, stokoe2005thephosphoinositide3kinase pages 1-3) |
| BP | phosphatidylinositol 3-kinase signaling | PI3Kδ-generated PIP3 recruits and activates AKT-linked signaling modules controlling downstream immune-cell responses. | Human / mouse / review synthesis | (ijspeert2024hyperactivationofthe pages 2-4, ijspeert2024hyperactivationofthe pages 1-2) |
| BP | B cell receptor signaling pathway | Genetic loss of p110δ causes a specific BCR signaling defect, indicating a nonredundant positive role downstream of the BCR/CD19 axis. | Mouse knockout | (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole pages 8-10, jou2002essentialnonredundantrole pages 1-2) |
| BP | intracellular calcium ion mobilization | Anti-IgM-induced Ca2+ mobilization in p110δ-deficient B cells is reduced to about 25% of wild type, supporting a role in BCR-triggered Ca2+ signaling. | Mouse knockout | (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole media 9f8002cf) |
| BP | B cell development | p110δ deficiency reduces mature peripheral B cells, causes a developmental block and loss of B1 cells, supporting annotation to B-cell developmental processes. | Mouse knockout | (jou2002essentialnonredundantrole pages 1-2, jou2002essentialnonredundantrole pages 2-4) |
| BP | B cell activation | p110δ-deficient B cells show impaired responses to BCR ligation and reduced activation-associated functional outputs. | Mouse knockout | (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole pages 2-4) |
| BP | B cell proliferation | Splenic p110δ-deficient B cells proliferate poorly in response to anti-IgM, anti-CD40 and LPS, while bypass stimulation is relatively preserved. | Mouse knockout | (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole pages 2-4) |
| BP | germinal center formation | Immunized p110δ-deficient mice fail to form splenic germinal centers, demonstrating a requirement for PI3Kδ in this humoral immune process. | Mouse knockout | (jou2002essentialnonredundantrole pages 1-2, jou2002essentialnonredundantrole media 9f8002cf) |
| BP | T-dependent humoral immune response | T-dependent antibody responses are absent in p110δ-deficient mice, with severe defects also seen for TI responses, supporting a role in antibody production pathways. | Mouse knockout | (jou2002essentialnonredundantrole pages 4-8, jou2002essentialnonredundantrole media 9f8002cf) |
| BP | AKT signaling / positive regulation of TOR signaling | Recent reviews and APDS-related studies place PI3Kδ upstream of AKT, mTORC1/S6 and FOXO regulation; pS6 elevation is used as a downstream readout of pathway activation. | Human patients / mouse models | (ijspeert2024hyperactivationofthe pages 2-4, nguyen2023humanpik3r1mutations pages 24-25, singh2024activatedpi3kδspecifically pages 11-13) |
| BP | regulatory T cell homeostasis | Balanced PI3Kδ activity is required in Tregs: hyperactive PI3Kδ increases Treg numbers but reduces fitness and functional stability, whereas insufficient signaling also impairs tolerance. | Mouse conditional GOF / review synthesis | (singh2024activatedpi3kδspecifically pages 3-4, singh2024activatedpi3kδspecifically pages 11-13, singh2024activatedpi3kδspecifically pages 1-3) |
| BP | immune tolerance / negative regulation of immune response | Treg-restricted activated PI3Kδ drives chronic inflammation, elevated IFN-γ, increased Tfh/GC responses and broad autoantibody production, indicating loss of tolerance when PI3Kδ is dysregulated. | Mouse conditional GOF | (singh2024activatedpi3kδspecifically pages 3-4, singh2024activatedpi3kδspecifically pages 10-11, singh2024activatedpi3kδspecifically pages 1-3) |
| BP | caveat: isoform redundancy and context dependence | Some PI3K outputs can be shared with other class I isoforms; p110δ is leukocyte-enriched but not absolutely exclusive, so annotations should favor immune-context evidence over broad generic signaling claims. | Curation note | (ijspeert2024hyperactivationofthe pages 1-2, wright2024theimportanceof pages 4-6, cant2024pi3kδpathwaydysregulation pages 1-3) |
| BP | caveat: inhibitor-based evidence can be confounded | PI3Kδ inhibitors differ in selectivity, mechanism and metabolites (e.g., ATP-competitive vs noncompetitive; off-target active metabolites), so pharmacology alone should not be over-weighted for direct GO assignment. | Curation note / cell-free and cellular pharmacology | (johnson2023ioa244isa pages 6-7, de2024leniolisibanovel pages 2-4, cant2024pi3kδpathwaydysregulation pages 13-14, johnson2023ioa244isa pages 15-16) |
Table: This table summarizes high-confidence, curator-facing GO annotation suggestions for human PIK3CD/p110δ, mapped to the strongest experimental evidence retrieved in this session. It highlights core molecular function, complex/localization, immune signaling processes, and key curation caveats.
References
(ijspeert2024hyperactivationofthe pages 2-4): Hanna IJspeert, Virgil A S H Dalm, Menno C van Zelm, and Emily S J Edwards. Hyperactivation of the pi3k pathway in inborn errors of immunity: current understanding and therapeutic perspectives. Immunotherapy Advances, Nov 2024. URL: https://doi.org/10.1093/immadv/ltae009, doi:10.1093/immadv/ltae009. This article has 11 citations.
(ijspeert2024hyperactivationofthe pages 1-2): Hanna IJspeert, Virgil A S H Dalm, Menno C van Zelm, and Emily S J Edwards. Hyperactivation of the pi3k pathway in inborn errors of immunity: current understanding and therapeutic perspectives. Immunotherapy Advances, Nov 2024. URL: https://doi.org/10.1093/immadv/ltae009, doi:10.1093/immadv/ltae009. This article has 11 citations.
(stokoe2005thephosphoinositide3kinase pages 1-3): David Stokoe. The phosphoinositide 3-kinase pathway and cancer. Expert Reviews in Molecular Medicine, 7:1-22, Jun 2005. URL: https://doi.org/10.1017/s1462399405009361, doi:10.1017/s1462399405009361. This article has 73 citations and is from a peer-reviewed journal.
(johnson2023ioa244isa pages 6-7): Zoë Johnson, Chiara Tarantelli, Elisa Civanelli, Luciano Cascione, Filippo Spriano, Amy Fraser, Pritom Shah, Tyzoon Nomanbhoy, Sara Napoli, Andrea Rinaldi, Karolina Niewola-Staszkowska, Michael Lahn, Dominique Perrin, Mathias Wenes, Denis Migliorini, Francesco Bertoni, Lars van der Veen, and Giusy Di Conza. Ioa-244 is a non–atp-competitive, highly selective, tolerable pi3k delta inhibitor that targets solid tumors and breaks immune tolerance. Cancer Research Communications, 3:576-591, Apr 2023. URL: https://doi.org/10.1158/2767-9764.crc-22-0477, doi:10.1158/2767-9764.crc-22-0477. This article has 33 citations and is from a peer-reviewed journal.
(jou2002essentialnonredundantrole pages 4-8): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(jou2002essentialnonredundantrole media 9f8002cf): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(jou2002essentialnonredundantrole pages 1-2): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(jou2002essentialnonredundantrole pages 2-4): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(jou2002essentialnonredundantrole media 37876baa): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(jou2002essentialnonredundantrole media 7d2b61ed): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(jou2002essentialnonredundantrole media 3b78ec57): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(singh2024activatedpi3kδspecifically pages 1-3): Akhilesh K. Singh, Fahd Al Qureshah, Travis Drow, Baidong Hou, and David J. Rawlings. Activated pi3kδ specifically perturbs mouse regulatory t cell homeostasis and function leading to immune dysregulation. Journal of immunology, 213:135-147, Jun 2024. URL: https://doi.org/10.4049/jimmunol.2400032, doi:10.4049/jimmunol.2400032. This article has 8 citations and is from a domain leading peer-reviewed journal.
(singh2024activatedpi3kδspecifically pages 3-4): Akhilesh K. Singh, Fahd Al Qureshah, Travis Drow, Baidong Hou, and David J. Rawlings. Activated pi3kδ specifically perturbs mouse regulatory t cell homeostasis and function leading to immune dysregulation. Journal of immunology, 213:135-147, Jun 2024. URL: https://doi.org/10.4049/jimmunol.2400032, doi:10.4049/jimmunol.2400032. This article has 8 citations and is from a domain leading peer-reviewed journal.
(singh2024activatedpi3kδspecifically pages 11-13): Akhilesh K. Singh, Fahd Al Qureshah, Travis Drow, Baidong Hou, and David J. Rawlings. Activated pi3kδ specifically perturbs mouse regulatory t cell homeostasis and function leading to immune dysregulation. Journal of immunology, 213:135-147, Jun 2024. URL: https://doi.org/10.4049/jimmunol.2400032, doi:10.4049/jimmunol.2400032. This article has 8 citations and is from a domain leading peer-reviewed journal.
(singh2024activatedpi3kδspecifically pages 10-11): Akhilesh K. Singh, Fahd Al Qureshah, Travis Drow, Baidong Hou, and David J. Rawlings. Activated pi3kδ specifically perturbs mouse regulatory t cell homeostasis and function leading to immune dysregulation. Journal of immunology, 213:135-147, Jun 2024. URL: https://doi.org/10.4049/jimmunol.2400032, doi:10.4049/jimmunol.2400032. This article has 8 citations and is from a domain leading peer-reviewed journal.
(johnson2023ioa244isa pages 13-14): Zoë Johnson, Chiara Tarantelli, Elisa Civanelli, Luciano Cascione, Filippo Spriano, Amy Fraser, Pritom Shah, Tyzoon Nomanbhoy, Sara Napoli, Andrea Rinaldi, Karolina Niewola-Staszkowska, Michael Lahn, Dominique Perrin, Mathias Wenes, Denis Migliorini, Francesco Bertoni, Lars van der Veen, and Giusy Di Conza. Ioa-244 is a non–atp-competitive, highly selective, tolerable pi3k delta inhibitor that targets solid tumors and breaks immune tolerance. Cancer Research Communications, 3:576-591, Apr 2023. URL: https://doi.org/10.1158/2767-9764.crc-22-0477, doi:10.1158/2767-9764.crc-22-0477. This article has 33 citations and is from a peer-reviewed journal.
(de2024leniolisibanovel pages 1-2): Surya K. De. Leniolisib: a novel treatment for activated phosphoinositide-3 kinase delta syndrome. Frontiers in Pharmacology, Feb 2024. URL: https://doi.org/10.3389/fphar.2024.1337436, doi:10.3389/fphar.2024.1337436. This article has 12 citations.
(cant2024pi3kδpathwaydysregulation pages 19-20): Andrew J. Cant, Anita Chandra, Ewen Munro, V. Koneti Rao, and Carrie L. Lucas. Pi3kδ pathway dysregulation and unique features of its inhibition by leniolisib in activated pi3kδ syndrome and beyond. The Journal of Allergy and Clinical Immunology: In Practice, 12:69-78, Jan 2024. URL: https://doi.org/10.1016/j.jaip.2023.09.016, doi:10.1016/j.jaip.2023.09.016. This article has 34 citations.
(cant2024pi3kδpathwaydysregulation pages 13-14): Andrew J. Cant, Anita Chandra, Ewen Munro, V. Koneti Rao, and Carrie L. Lucas. Pi3kδ pathway dysregulation and unique features of its inhibition by leniolisib in activated pi3kδ syndrome and beyond. The Journal of Allergy and Clinical Immunology: In Practice, 12:69-78, Jan 2024. URL: https://doi.org/10.1016/j.jaip.2023.09.016, doi:10.1016/j.jaip.2023.09.016. This article has 34 citations.
(cant2024pi3kδpathwaydysregulation pages 1-3): Andrew J. Cant, Anita Chandra, Ewen Munro, V. Koneti Rao, and Carrie L. Lucas. Pi3kδ pathway dysregulation and unique features of its inhibition by leniolisib in activated pi3kδ syndrome and beyond. The Journal of Allergy and Clinical Immunology: In Practice, 12:69-78, Jan 2024. URL: https://doi.org/10.1016/j.jaip.2023.09.016, doi:10.1016/j.jaip.2023.09.016. This article has 34 citations.
(berglund2024modulatingthepi3k pages 8-8): Lucinda J. Berglund. Modulating the pi3k signalling pathway in activated pi3k delta syndrome: a clinical perspective. Journal of Clinical Immunology, Dec 2024. URL: https://doi.org/10.1007/s10875-023-01626-0, doi:10.1007/s10875-023-01626-0. This article has 20 citations and is from a domain leading peer-reviewed journal.
(jou2002essentialnonredundantrole pages 8-10): Shiann-Tarng Jou, Nick Carpino, Yutaka Takahashi, Roland Piekorz, Jyh-Rong Chao, Neena Carpino, Demin Wang, and James N. Ihle. Essential, nonredundant role for the phosphoinositide 3-kinase p110δ in signaling by the b-cell receptor complex. Molecular and Cellular Biology, 22:8580-8591, Dec 2002. URL: https://doi.org/10.1128/mcb.22.24.8580-8591.2002, doi:10.1128/mcb.22.24.8580-8591.2002. This article has 480 citations and is from a domain leading peer-reviewed journal.
(nguyen2023humanpik3r1mutations pages 24-25): Tina Nguyen, Anthony Lau, Julia Bier, Kristen C. Cooke, Helen Lenthall, Stephanie Ruiz-Diaz, Danielle T. Avery, Henry Brigden, David Zahra, William A Sewell, Luke Droney, Satoshi Okada, Takaki Asano, Hassan Abolhassani, Zahra Chavoshzadeh, Roshini S. Abraham, Nipunie Rajapakse, Eric W. Klee, Joseph A. Church, Andrew Williams, Melanie Wong, Christoph Burkhart, Gulbu Uzel, David R. Croucher, David E. James, Cindy S. Ma, Robert Brink, Stuart G. Tangye, and Elissa K. Deenick. Human pik3r1 mutations disrupt lymphocyte differentiation to cause activated pi3kδ syndrome 2. The Journal of Experimental Medicine, Mar 2023. URL: https://doi.org/10.1084/jem.20221020, doi:10.1084/jem.20221020. This article has 32 citations.
(wright2024theimportanceof pages 4-6): Brock Wright, Samuel King, and Cenk Suphioglu. The importance of phosphoinositide 3-kinase in neuroinflammation. International Journal of Molecular Sciences, 25:11638, Oct 2024. URL: https://doi.org/10.3390/ijms252111638, doi:10.3390/ijms252111638. This article has 43 citations.
(de2024leniolisibanovel pages 2-4): Surya K. De. Leniolisib: a novel treatment for activated phosphoinositide-3 kinase delta syndrome. Frontiers in Pharmacology, Feb 2024. URL: https://doi.org/10.3389/fphar.2024.1337436, doi:10.3389/fphar.2024.1337436. This article has 12 citations.
(johnson2023ioa244isa pages 15-16): Zoë Johnson, Chiara Tarantelli, Elisa Civanelli, Luciano Cascione, Filippo Spriano, Amy Fraser, Pritom Shah, Tyzoon Nomanbhoy, Sara Napoli, Andrea Rinaldi, Karolina Niewola-Staszkowska, Michael Lahn, Dominique Perrin, Mathias Wenes, Denis Migliorini, Francesco Bertoni, Lars van der Veen, and Giusy Di Conza. Ioa-244 is a non–atp-competitive, highly selective, tolerable pi3k delta inhibitor that targets solid tumors and breaks immune tolerance. Cancer Research Communications, 3:576-591, Apr 2023. URL: https://doi.org/10.1158/2767-9764.crc-22-0477, doi:10.1158/2767-9764.crc-22-0477. This article has 33 citations and is from a peer-reviewed journal.
Generated Falcon deep research at PIK3CD-deep-research-falcon.md and used it with
UniProt plus cached publications to complete the initialized GO review.
Core synthesis: PIK3CD encodes p110delta, a leukocyte-enriched class IA PI3K
catalytic subunit. The central molecular function is PI(4,5)P2 3-kinase
activity producing PIP3 in p85-family regulatory complexes at receptor-activated
membranes. Falcon summarizes this as: [file:human/PIK3CD/PIK3CD-deep-research-falcon.md
"PIK3CD encodes the catalytic subunit p110δ of class IA phosphoinositide
3-kinase (PI3Kδ), a lipid kinase that produces PI(3,4,5)P3 (PIP3) at
membranes downstream of receptor signaling in immune cells, particularly in
lymphocytes."] Direct biochemical work also reports that recombinant p110delta
phosphorylates phosphatidylinositol and associates with p85 PMID:9235916.
The most informative process terms are PI3K/AKT signaling plus immune receptor
contexts, especially BCR, TCR, and CD28. Falcon frames the receptor context as
[file:human/PIK3CD/PIK3CD-deep-research-falcon.md "In immune cells, class IA PI3K
(including p110δ) propagates signaling downstream of BCR, TCR, CD28, ICOS,
CD19, BAFF-R, CD40"] and UniProt separately records BCR and TCR requirements
[file:human/PIK3CD/PIK3CD-uniprot.txt "Required for B-cell receptor (BCR) signaling."]
[file:human/PIK3CD/PIK3CD-uniprot.txt "Required for T-cell receptor (TCR) signaling."].
Broad immune, chemotaxis, endothelial migration, angiogenesis, mast-cell,
neutrophil, NK-cell, and cytokine-production annotations were retained as
non-core where supported. The main evidence is that PI3Kdelta participates in
multiple leukocyte outputs PMID:20940048 and myeloid
activities PMID:20940048.
Several terms were deliberately modified or marked over-annotated:
id: O00329
gene_symbol: PIK3CD
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'PIK3CD encodes p110delta, the leukocyte-enriched catalytic subunit of class
IA phosphoinositide 3-kinase delta. In p85-family regulatory complexes, p110delta phosphorylates
membrane phosphoinositides, especially PI(4,5)P2, to generate PIP3 downstream of immune
receptors including BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40, Fc receptors, and cytokine/growth-factor
receptors. The core curatable function is PIP3-producing lipid kinase activity in PI3K/AKT
immune receptor signaling; broad immune phenotypes, chemotaxis, angiogenesis, and migration
annotations are supported contextual outputs rather than the core molecular function.'
alternative_products:
- name: 1 (p110-delta)
id: O00329-1
- name: 2 (p37-delta)
id: O00329-2
sequence_note: VSP_044409, VSP_044410
existing_annotations:
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0016477
label: cell migration
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Supported cell-migration role in specific leukocyte and glioma contexts,
but non-core relative to lipid kinase signaling.
action: KEEP_AS_NON_CORE
reason: PIK3CD knockdown decreases glioma-cell migration and PI3Kdelta also affects
leukocyte migration; these are downstream context-specific outputs rather than the
core function.
supported_by:
- reference_id: PMID:22079609
supporting_text: Interestingly, knockdown of p110δ decreased the cell migration
and invasion ability of all GBM cell lines tested.
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- term:
id: GO:0005942
label: phosphatidylinositol 3-kinase complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: The complex assignment is valid but should use the more specific class IA
phosphatidylinositol 3-kinase complex term.
action: MODIFY
reason: PIK3CD is not just any PI3K-complex component; it is the p110delta catalytic
subunit of class IA p85-family regulatory complexes. GO:0005943 captures the
correct complex subtype.
proposed_replacement_terms:
- id: GO:0005943
label: phosphatidylinositol 3-kinase complex, class IA
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated
PIP3.
action: ACCEPT
reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This
pathway term captures the central signaling output of PI3Kdelta even when the
initiating receptor or cell type differs.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: '**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide
3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes
downstream of receptor signaling in immune cells, particularly in lymphocytes.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- term:
id: GO:0036092
label: phosphatidylinositol-3-phosphate biosynthetic process
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: The PI3P biosynthetic-process term is too specific for a class
III/VPS34-like product and is not the best process term for PIK3CD.
action: MODIFY
reason: PIK3CD/p110delta primarily generates PIP3 from PI(4,5)P2 in class IA
receptor signaling. A broader phosphatidylinositol phosphate biosynthetic process
term better reflects the current GO vocabulary without implying class III
PI3P-centered biology.
proposed_replacement_terms:
- id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: Reactome:R-HSA-389158
supporting_text: Upon binding to CD28, the PI3K enzyme catalyzes the
phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate
phosphatidylinositol 3,4,5-trisphosphate (PIP3).
- term:
id: GO:0048015
label: phosphatidylinositol-mediated signaling
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: The phosphatidylinositol-mediated signaling term is correct but too broad
for PIK3CD.
action: MODIFY
reason: PIK3CD is specifically a class IA PIP3-producing PI3K that feeds PI3K/AKT
receptor signaling, so the more specific PI3K/AKT signal-transduction term is
preferred.
proposed_replacement_terms:
- id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: '**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide
3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes
downstream of receptor signaling in immune cells, particularly in lymphocytes.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0016303
label: 1-phosphatidylinositol-3-kinase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic
subunit.
action: ACCEPT
reason: This parent PI3K activity term is valid for p110delta, although GO:0046934
is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
supported_by:
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- term:
id: GO:0035005
label: 1-phosphatidylinositol-4-phosphate 3-kinase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: Supported phosphoinositide 3-kinase substrate activity, but PI4P
phosphorylation is not the primary curatable core activity for PIK3CD.
action: KEEP_AS_NON_CORE
reason: Class I PI3Kdelta can act on phosphorylated phosphoinositides, and Reactome
includes PIK3CD complexes in PI4P-to-PI(3,4)P2 reactions. The canonical core
activity remains PI(4,5)P2-to-PIP3.
supported_by:
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- reference_id: Reactome:R-HSA-1676109
supporting_text: These complexes along with phosphatidylinositol-4-phosphate
3-kinase C2 domain-containing subunits alpha (PIK3C2A), beta (PIK3C2B), and
gamma (PIK3C2G) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to
phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2).
- term:
id: GO:0000166
label: nucleotide binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: The nucleotide-binding annotation is too generic for a lipid kinase and
should be narrowed to ATP binding.
action: MODIFY
reason: PIK3CD catalysis uses ATP; the broad nucleotide-binding term loses the
catalytic context and is less informative than GO:0005524 ATP binding or the
catalytic PI(4,5)P2 3-kinase MF.
proposed_replacement_terms:
- id: GO:0005524
label: ATP binding
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- term:
id: GO:0002250
label: adaptive immune response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Supported adaptive-immune output, but this is a systems-level consequence
of PI3Kdelta immune receptor signaling rather than the core molecular function.
action: KEEP_AS_NON_CORE
reason: Human disease genetics and leukocyte studies support a role in adaptive
immunity, but the core function should remain PIP3-producing class IA PI3K
signaling.
supported_by:
- reference_id: PMID:27616589
supporting_text: Here, we review the roles of PI3Kδ in adaptive immunity, describe
the clinical manifestations and mechanisms of disease in APDS and highlight new
insights into PI3Kδ gleaned from these patients, as well as implications of
these findings for clinical therapy.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0002376
label: immune system process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Correct directionally but too broad to be useful for PIK3CD curation.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD has immune functions, but GO:0002376 is a very broad parent term.
More informative annotations are BCR/TCR signaling, PI3K/AKT signaling, and
specific leukocyte activation/migration processes.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0002443
label: leukocyte mediated immunity
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Supported leukocyte/immune response involvement, but non-core and broad
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PIK3CD is leukocyte-enriched and affects immune responses, yet this broad
immune-process term should not define the core function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- reference_id: PMID:27616589
supporting_text: Here, we review the roles of PI3Kδ in adaptive immunity, describe
the clinical manifestations and mechanisms of disease in APDS and highlight new
insights into PI3Kδ gleaned from these patients, as well as implications of
these findings for clinical therapy.
- term:
id: GO:0005524
label: ATP binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: ATP binding is valid for the catalytic kinase domain, but it is generic
relative to the core lipid kinase activity.
action: KEEP_AS_NON_CORE
reason: ATP is required for PI3Kdelta catalysis, yet ATP binding alone is not a
specific description of the gene product function.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005829
label: cytosol
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005943
label: phosphatidylinositol 3-kinase complex, class IA
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Correct class IA PI3K complex annotation for p110delta/p85-family
regulatory assemblies.
action: ACCEPT
reason: This is the most specific existing CC term for PIK3CD complex membership and
is supported by ComplexPortal entries and synthesis of the class IA p110delta-p85
regulatory complex.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: Reactome:R-HSA-2316434
supporting_text: In unstimulated cells, PI3K class IA exists as an inactive
heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3)
and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD).
- term:
id: GO:0006629
label: lipid metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: The lipid metabolic process term is directionally correct but too broad for
PIK3CD.
action: MODIFY
reason: PIK3CD is specifically a phosphoinositide lipid kinase that produces
3-phosphoinositides/PIP3 in signaling contexts; phosphatidylinositol phosphate
biosynthesis is the more informative same-aspect process replacement, while the
specific PI(4,5)P2 3-kinase molecular function is handled separately.
proposed_replacement_terms:
- id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0006935
label: chemotaxis
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: The generic chemotaxis annotation should be narrowed to the specific
leukocyte chemotaxis processes supported for PIK3CD.
action: MODIFY
reason: The evidence supports T-cell, B-cell, neutrophil, and mast-cell chemotaxis
contexts rather than chemotaxis as a broad parent term.
proposed_replacement_terms:
- id: GO:0010818
label: T cell chemotaxis
- id: GO:0035754
label: B cell chemotaxis
- id: GO:0030593
label: neutrophil chemotaxis
- id: GO:0002551
label: mast cell chemotaxis
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0006954
label: inflammatory response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: Supported inflammatory-response involvement, but it is a downstream
physiological output of PI3Kdelta activity.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta disruption alters inflammatory responses in vivo and PI3K lipid
messengers control leukocyte signaling, but inflammation is a non-core
phenotype/process relative to lipid kinase signaling.
supported_by:
- reference_id: PMID:17290298
supporting_text: Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second
messengers that control an array of intracellular signalling pathways that are
known to have important roles in leukocytes.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0007166
label: cell surface receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: The broad cell-surface receptor signaling annotation should be narrowed to
the immune receptor signaling pathways where PIK3CD has strong support.
action: MODIFY
reason: PIK3CD acts downstream of immune receptors such as BCR, TCR, and CD28. Those
terms are more informative and better supported than the generic cell-surface
receptor signaling parent.
proposed_replacement_terms:
- id: GO:0050853
label: B cell receptor signaling pathway
- id: GO:0050852
label: T cell receptor signaling pathway
- id: GO:0031295
label: T cell costimulation
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for B-cell receptor (BCR) signaling.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for T-cell receptor (TCR) signaling.
- term:
id: GO:0010595
label: positive regulation of endothelial cell migration
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Supported endothelial/angiogenesis context, but non-core and
tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
action: KEEP_AS_NON_CORE
reason: Cultured endothelial-cell work supports VEGF-induced Akt activation,
proliferation, migration, tube formation, and retinal angiogenesis. This is a real
contextual role, not the primary leukocyte-enriched core function.
supported_by:
- reference_id: PMID:31915155
supporting_text: Using genetic and pharmacological approaches, we show that p110δ
activity in cultured ECs controls Akt activation, cell proliferation, migration,
and tube formation induced by vascular endothelial growth factor, basic
fibroblast growth factor, and epidermal growth factor.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Over-annotation to positive regulation of gene expression. The available
PIK3CD evidence supports upstream PI3K/AKT signaling more directly than this
distal transcriptional-output term.
action: MARK_AS_OVER_ANNOTATED
reason: Gene-expression changes can occur downstream of PI3K/AKT/FOXO signaling, but
the evidence supports this as a distal pathway output requiring careful
attribution rather than a direct core PIK3CD function. This broad distal term
should not be retained as a core annotation.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: It highlights pathway antagonism by PTEN/SHIP and connects
FOXO-regulated transcription (e.g., immune differentiation programs) to PI3K
signaling outputs (useful for downstream BP annotations, but requires careful
evidence attribution if annotating those distal effects).
- term:
id: GO:0016301
label: kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: The generic enzyme-activity annotation is valid only as a distant parent
and should be replaced by the specific lipid kinase activity.
action: MODIFY
reason: PIK3CD is not merely a generic kinase/transferase; the evidence supports
phosphoinositide 3-kinase activity, especially PI(4,5)P2 3-kinase activity.
proposed_replacement_terms:
- id: GO:0046934
label: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- term:
id: GO:0016303
label: 1-phosphatidylinositol-3-kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic
subunit.
action: ACCEPT
reason: This parent PI3K activity term is valid for p110delta, although GO:0046934
is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
supported_by:
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- term:
id: GO:0016740
label: transferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: The generic enzyme-activity annotation is valid only as a distant parent
and should be replaced by the specific lipid kinase activity.
action: MODIFY
reason: PIK3CD is not merely a generic kinase/transferase; the evidence supports
phosphoinositide 3-kinase activity, especially PI(4,5)P2 3-kinase activity.
proposed_replacement_terms:
- id: GO:0046934
label: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- term:
id: GO:0022603
label: regulation of anatomical structure morphogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Over-annotation to broad developmental, morphogenesis, or adhesion
regulation terms.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but
these broad regulation terms over-generalize downstream effects and obscure the
better-supported PI3Kdelta receptor-signaling biology.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0030154
label: cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: The generic cell differentiation annotation should be narrowed to the
specific leukocyte differentiation processes supported for PIK3CD.
action: MODIFY
reason: The evidence supports B-cell, T-cell, NK-cell, and mast-cell differentiation
contexts rather than undifferentiated cell differentiation as a generic parent.
proposed_replacement_terms:
- id: GO:0030183
label: B cell differentiation
- id: GO:0030217
label: T cell differentiation
- id: GO:0001779
label: natural killer cell differentiation
- id: GO:0060374
label: mast cell differentiation
supported_by:
- reference_id: PMID:20200404
supporting_text: Thus, we provide novel evidence that p110gamma and p110delta have
overlapping and cell-extrinsic roles in the development, peripheral maintenance,
and function of B cells.
- reference_id: PMID:17371229
supporting_text: In addition, p110delta regulates the differentiation of
peripheral Th (helper T-cells) towards the Th1 and Th2 lineages.
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- term:
id: GO:0030155
label: regulation of cell adhesion
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Over-annotation to broad developmental, morphogenesis, or adhesion
regulation terms.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but
these broad regulation terms over-generalize downstream effects and obscure the
better-supported PI3Kdelta receptor-signaling biology.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0033031
label: positive regulation of neutrophil apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Supported neutrophil-death/apoptotic-process annotation, but non-core and
context-dependent.
action: KEEP_AS_NON_CORE
reason: FcαRI-triggered neutrophil death requires class IA PI3K signaling in
inflammatory contexts. This supports the annotation as a non-core immune effector
process.
supported_by:
- reference_id: PMID:25339672
supporting_text: preactivation with cytokines or TLR agonists in vitro enhanced
FcαRI-mediated death by additional recruitment of caspase-independent pathways,
but this required PI3K class IA and MAPK signaling.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0042113
label: B cell activation
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Supported B-cell activation/function annotation, but downstream of the more
core BCR signaling role.
action: KEEP_AS_NON_CORE
reason: PIK3CD is important for B-cell development and function. B-cell activation
is real, but BCR signaling and PI3K/AKT signaling are the more precise core
process annotations.
supported_by:
- reference_id: PMID:20200404
supporting_text: Thus, we provide novel evidence that p110gamma and p110delta have
overlapping and cell-extrinsic roles in the development, peripheral maintenance,
and function of B cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for B-cell receptor (BCR) signaling.
- term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated
PIP3.
action: ACCEPT
reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This
pathway term captures the central signaling output of PI3Kdelta even when the
initiating receptor or cell type differs.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: '**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide
3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes
downstream of receptor signaling in immune cells, particularly in lymphocytes.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- term:
id: GO:0045087
label: innate immune response
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Supported innate-immune involvement, but this is a broad non-core
immune-system output.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta contributes to myeloid and innate leukocyte activities, but the
precise core function is receptor-linked PIP3 production rather than innate
immunity as a whole.
supported_by:
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- reference_id: PMID:17290298
supporting_text: Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second
messengers that control an array of intracellular signalling pathways that are
known to have important roles in leukocytes.
- term:
id: GO:0046854
label: phosphatidylinositol phosphate biosynthetic process
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: Supported core process output of PI3Kdelta lipid kinase activity.
action: ACCEPT
reason: PIK3CD produces 3-phosphoinositides, especially PIP3, as the biochemical
product of its class IA lipid kinase activity. This process term is broader than
an ideal PIP3-biosynthesis term but is correct.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: Reactome:R-HSA-389158
supporting_text: Upon binding to CD28, the PI3K enzyme catalyzes the
phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate
phosphatidylinositol 3,4,5-trisphosphate (PIP3).
- term:
id: GO:0046934
label: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: 'Core specific molecular function: p110delta phosphorylates PI(4,5)P2 to generate
PIP3.'
action: ACCEPT
reason: PI(4,5)P2 3-kinase activity is the specific catalytic activity that drives
PI3Kdelta receptor signaling and PIP3-dependent AKT pathway recruitment.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: Reactome:R-HSA-389158
supporting_text: Upon binding to CD28, the PI3K enzyme catalyzes the
phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate
phosphatidylinositol 3,4,5-trisphosphate (PIP3).
- term:
id: GO:0051094
label: positive regulation of developmental process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Over-annotation to broad developmental, morphogenesis, or adhesion
regulation terms.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but
these broad regulation terms over-generalize downstream effects and obscure the
better-supported PI3Kdelta receptor-signaling biology.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0051240
label: positive regulation of multicellular organismal process
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Over-annotation to broad developmental, morphogenesis, or adhesion
regulation terms.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but
these broad regulation terms over-generalize downstream effects and obscure the
better-supported PI3Kdelta receptor-signaling biology.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:2000026
label: regulation of multicellular organismal development
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Over-annotation to broad developmental, morphogenesis, or adhesion
regulation terms.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD has specific leukocyte, endothelial, and migration phenotypes, but
these broad regulation terms over-generalize downstream effects and obscure the
better-supported PI3Kdelta receptor-signaling biology.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21827948
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22020336
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24165795
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31031754
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:35271311
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:40205054
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0005829
label: cytosol
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32606397
review:
summary: Protein binding is an uninformative over-annotation for PIK3CD.
action: MARK_AS_OVER_ANNOTATED
reason: PIK3CD does interact with p85-family regulatory subunits and other signaling
proteins, but GO:0005515 does not capture the meaningful function. The informative
annotations are class IA PI3K complex membership and phosphoinositide kinase
activity.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- term:
id: GO:0031295
label: T cell costimulation
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389356
review:
summary: Supported CD28/T-cell costimulation context for PI3Kdelta signaling.
action: ACCEPT
reason: CD28 is a direct immune receptor context in which PI3K participates in
costimulatory signaling and PIP3 generation. This is part of the core
immune-receptor signaling frame for PIK3CD.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: Reactome:R-HSA-389356
supporting_text: The cytoplasmic tail of CD28, upon ligand binding, undergoes
phosphorylation by Src family kinases like LCK and FYN, triggering downstream
signaling pathways involving PI3K, VAV-1, Tec family kinases, AKT, and other
adaptor proteins (Sharpe & Freeman 2002; Chen & Flies 2013).
- reference_id: Reactome:R-HSA-389158
supporting_text: Upon binding to CD28, the PI3K enzyme catalyzes the
phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate
phosphatidylinositol 3,4,5-trisphosphate (PIP3).
- term:
id: GO:0046934
label: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389158
review:
summary: 'Core specific molecular function: p110delta phosphorylates PI(4,5)P2 to generate
PIP3.'
action: ACCEPT
reason: PI(4,5)P2 3-kinase activity is the specific catalytic activity that drives
PI3Kdelta receptor signaling and PIP3-dependent AKT pathway recruitment.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: Reactome:R-HSA-389158
supporting_text: Upon binding to CD28, the PI3K enzyme catalyzes the
phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate
phosphatidylinositol 3,4,5-trisphosphate (PIP3).
- term:
id: GO:0006955
label: immune response
evidence_type: NAS
original_reference_id: PMID:27616589
review:
summary: Supported leukocyte/immune response involvement, but non-core and broad
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PIK3CD is leukocyte-enriched and affects immune responses, yet this broad
immune-process term should not define the core function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- reference_id: PMID:27616589
supporting_text: Here, we review the roles of PI3Kδ in adaptive immunity, describe
the clinical manifestations and mechanisms of disease in APDS and highlight new
insights into PI3Kδ gleaned from these patients, as well as implications of
these findings for clinical therapy.
- term:
id: GO:0030183
label: B cell differentiation
evidence_type: NAS
original_reference_id: PMID:20200404
review:
summary: Supported B-cell differentiation/development role, but non-core relative to
PI3Kdelta catalytic signaling.
action: KEEP_AS_NON_CORE
reason: B-cell developmental phenotypes are well supported, but they are downstream
organism/cell lineage consequences of PIP3-producing PI3Kdelta signaling.
supported_by:
- reference_id: PMID:20200404
supporting_text: Thus, we provide novel evidence that p110gamma and p110delta have
overlapping and cell-extrinsic roles in the development, peripheral maintenance,
and function of B cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for B-cell receptor (BCR) signaling.
- term:
id: GO:0030217
label: T cell differentiation
evidence_type: NAS
original_reference_id: PMID:17371229
review:
summary: Supported T-cell differentiation role, but non-core relative to
receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: T-cell differentiation is a supported immune-cell outcome of p110delta
activity, not the core molecular function itself.
supported_by:
- reference_id: PMID:17371229
supporting_text: In addition, p110delta regulates the differentiation of
peripheral Th (helper T-cells) towards the Th1 and Th2 lineages.
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- term:
id: GO:0038084
label: vascular endothelial growth factor signaling pathway
evidence_type: IGI
original_reference_id: PMID:31915155
review:
summary: Supported endothelial/angiogenesis context, but non-core and
tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
action: KEEP_AS_NON_CORE
reason: Cultured endothelial-cell work supports VEGF-induced Akt activation,
proliferation, migration, tube formation, and retinal angiogenesis. This is a real
contextual role, not the primary leukocyte-enriched core function.
supported_by:
- reference_id: PMID:31915155
supporting_text: Using genetic and pharmacological approaches, we show that p110δ
activity in cultured ECs controls Akt activation, cell proliferation, migration,
and tube formation induced by vascular endothelial growth factor, basic
fibroblast growth factor, and epidermal growth factor.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- term:
id: GO:0010595
label: positive regulation of endothelial cell migration
evidence_type: IGI
original_reference_id: PMID:31915155
review:
summary: Supported endothelial/angiogenesis context, but non-core and
tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
action: KEEP_AS_NON_CORE
reason: Cultured endothelial-cell work supports VEGF-induced Akt activation,
proliferation, migration, tube formation, and retinal angiogenesis. This is a real
contextual role, not the primary leukocyte-enriched core function.
supported_by:
- reference_id: PMID:31915155
supporting_text: Using genetic and pharmacological approaches, we show that p110δ
activity in cultured ECs controls Akt activation, cell proliferation, migration,
and tube formation induced by vascular endothelial growth factor, basic
fibroblast growth factor, and epidermal growth factor.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- term:
id: GO:0001938
label: positive regulation of endothelial cell proliferation
evidence_type: IGI
original_reference_id: PMID:31915155
review:
summary: Supported endothelial/angiogenesis context, but non-core and
tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
action: KEEP_AS_NON_CORE
reason: Cultured endothelial-cell work supports VEGF-induced Akt activation,
proliferation, migration, tube formation, and retinal angiogenesis. This is a real
contextual role, not the primary leukocyte-enriched core function.
supported_by:
- reference_id: PMID:31915155
supporting_text: Using genetic and pharmacological approaches, we show that p110δ
activity in cultured ECs controls Akt activation, cell proliferation, migration,
and tube formation induced by vascular endothelial growth factor, basic
fibroblast growth factor, and epidermal growth factor.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence_type: IGI
original_reference_id: PMID:31915155
review:
summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated
PIP3.
action: ACCEPT
reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This
pathway term captures the central signaling output of PI3Kdelta even when the
initiating receptor or cell type differs.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: '**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide
3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes
downstream of receptor signaling in immune cells, particularly in lymphocytes.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- term:
id: GO:0045766
label: positive regulation of angiogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Supported endothelial/angiogenesis context, but non-core and
tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
action: KEEP_AS_NON_CORE
reason: Cultured endothelial-cell work supports VEGF-induced Akt activation,
proliferation, migration, tube formation, and retinal angiogenesis. This is a real
contextual role, not the primary leukocyte-enriched core function.
supported_by:
- reference_id: PMID:31915155
supporting_text: Using genetic and pharmacological approaches, we show that p110δ
activity in cultured ECs controls Akt activation, cell proliferation, migration,
and tube formation induced by vascular endothelial growth factor, basic
fibroblast growth factor, and epidermal growth factor.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- term:
id: GO:1905278
label: positive regulation of epithelial tube formation
evidence_type: IGI
original_reference_id: PMID:31915155
review:
summary: Supported endothelial/angiogenesis context, but non-core and
tissue/pathology-specific relative to PI3Kdelta immune receptor signaling.
action: KEEP_AS_NON_CORE
reason: Cultured endothelial-cell work supports VEGF-induced Akt activation,
proliferation, migration, tube formation, and retinal angiogenesis. This is a real
contextual role, not the primary leukocyte-enriched core function.
supported_by:
- reference_id: PMID:31915155
supporting_text: Using genetic and pharmacological approaches, we show that p110δ
activity in cultured ECs controls Akt activation, cell proliferation, migration,
and tube formation induced by vascular endothelial growth factor, basic
fibroblast growth factor, and epidermal growth factor.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- term:
id: GO:0033031
label: positive regulation of neutrophil apoptotic process
evidence_type: IMP
original_reference_id: PMID:25339672
review:
summary: Supported neutrophil-death/apoptotic-process annotation, but non-core and
context-dependent.
action: KEEP_AS_NON_CORE
reason: FcαRI-triggered neutrophil death requires class IA PI3K signaling in
inflammatory contexts. This supports the annotation as a non-core immune effector
process.
supported_by:
- reference_id: PMID:25339672
supporting_text: preactivation with cytokines or TLR agonists in vitro enhanced
FcαRI-mediated death by additional recruitment of caspase-independent pathways,
but this required PI3K class IA and MAPK signaling.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence_type: IMP
original_reference_id: PMID:25339672
review:
summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated
PIP3.
action: ACCEPT
reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This
pathway term captures the central signaling output of PI3Kdelta even when the
initiating receptor or cell type differs.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: '**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide
3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes
downstream of receptor signaling in immune cells, particularly in lymphocytes.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- term:
id: GO:0001779
label: natural killer cell differentiation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported NK-cell differentiation role, but non-core relative to PI3Kdelta
catalytic signaling.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta participates in NK-cell development and migration, but this is a
leukocyte-specific cellular outcome rather than the core lipid kinase function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- term:
id: GO:0001819
label: positive regulation of cytokine production
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported cytokine-production role, but non-core and downstream of immune
receptor signaling.
action: KEEP_AS_NON_CORE
reason: Cytokine-production changes are leukocyte outputs of PI3Kdelta signaling,
not the primary biochemical function.
supported_by:
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for T-cell receptor (TCR) signaling.
- term:
id: GO:0002250
label: adaptive immune response
evidence_type: TAS
original_reference_id: PMID:17290298
review:
summary: Supported adaptive-immune output, but this is a systems-level consequence
of PI3Kdelta immune receptor signaling rather than the core molecular function.
action: KEEP_AS_NON_CORE
reason: Human disease genetics and leukocyte studies support a role in adaptive
immunity, but the core function should remain PIP3-producing class IA PI3K
signaling.
supported_by:
- reference_id: PMID:27616589
supporting_text: Here, we review the roles of PI3Kδ in adaptive immunity, describe
the clinical manifestations and mechanisms of disease in APDS and highlight new
insights into PI3Kδ gleaned from these patients, as well as implications of
these findings for clinical therapy.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0002551
label: mast cell chemotaxis
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta affects migration of multiple leukocyte types, but these are
cell-type-specific outputs of the core PIP3-generating immune signaling function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0002679
label: respiratory burst involved in defense response
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported neutrophil respiratory-burst role, but non-core relative to the
catalytic PI3Kdelta signaling function.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta contributes to neutrophil respiratory burst as a myeloid effector
output, but this is not the core molecular function.
supported_by:
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0006954
label: inflammatory response
evidence_type: TAS
original_reference_id: PMID:17290298
review:
summary: Supported inflammatory-response involvement, but it is a downstream
physiological output of PI3Kdelta activity.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta disruption alters inflammatory responses in vivo and PI3K lipid
messengers control leukocyte signaling, but inflammation is a non-core
phenotype/process relative to lipid kinase signaling.
supported_by:
- reference_id: PMID:17290298
supporting_text: Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second
messengers that control an array of intracellular signalling pathways that are
known to have important roles in leukocytes.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0006954
label: inflammatory response
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported inflammatory-response involvement, but it is a downstream
physiological output of PI3Kdelta activity.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta disruption alters inflammatory responses in vivo and PI3K lipid
messengers control leukocyte signaling, but inflammation is a non-core
phenotype/process relative to lipid kinase signaling.
supported_by:
- reference_id: PMID:17290298
supporting_text: Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second
messengers that control an array of intracellular signalling pathways that are
known to have important roles in leukocytes.
- reference_id: PMID:20940048
supporting_text: As a result of the broad effects of PI3Kδ in leukocyte functions,
the disruption of PI3Kδ expression or activity leads to decreased inflammatory
and immune responses in vivo.
- term:
id: GO:0010818
label: T cell chemotaxis
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta affects migration of multiple leukocyte types, but these are
cell-type-specific outputs of the core PIP3-generating immune signaling function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0016303
label: 1-phosphatidylinositol-3-kinase activity
evidence_type: TAS
original_reference_id: PMID:17290298
review:
summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic
subunit.
action: ACCEPT
reason: This parent PI3K activity term is valid for p110delta, although GO:0046934
is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
supported_by:
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- term:
id: GO:0030101
label: natural killer cell activation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported NK-cell activation context, but non-core relative to
receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: NK-cell activation is a supported immune output; the central curatable
function remains PI3Kdelta PIP3 production in leukocyte signaling.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- term:
id: GO:0030217
label: T cell differentiation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported T-cell differentiation role, but non-core relative to
receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: T-cell differentiation is a supported immune-cell outcome of p110delta
activity, not the core molecular function itself.
supported_by:
- reference_id: PMID:17371229
supporting_text: In addition, p110delta regulates the differentiation of
peripheral Th (helper T-cells) towards the Th1 and Th2 lineages.
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- term:
id: GO:0030593
label: neutrophil chemotaxis
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta affects migration of multiple leukocyte types, but these are
cell-type-specific outputs of the core PIP3-generating immune signaling function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0035747
label: natural killer cell chemotaxis
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta affects migration of multiple leukocyte types, but these are
cell-type-specific outputs of the core PIP3-generating immune signaling function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0035754
label: B cell chemotaxis
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta affects migration of multiple leukocyte types, but these are
cell-type-specific outputs of the core PIP3-generating immune signaling function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0042110
label: T cell activation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported T-cell activation/function annotation, but downstream of the more
core TCR/CD28 signaling role.
action: KEEP_AS_NON_CORE
reason: PIK3CD contributes to T-cell development, activation, and migration. The
T-cell activation process is supported but is a cellular outcome of the core
TCR/CD28 PI3K signaling function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for T-cell receptor (TCR) signaling.
- term:
id: GO:0042113
label: B cell activation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported B-cell activation/function annotation, but downstream of the more
core BCR signaling role.
action: KEEP_AS_NON_CORE
reason: PIK3CD is important for B-cell development and function. B-cell activation
is real, but BCR signaling and PI3K/AKT signaling are the more precise core
process annotations.
supported_by:
- reference_id: PMID:20200404
supporting_text: Thus, we provide novel evidence that p110gamma and p110delta have
overlapping and cell-extrinsic roles in the development, peripheral maintenance,
and function of B cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for B-cell receptor (BCR) signaling.
- term:
id: GO:0043303
label: mast cell degranulation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported mast-cell degranulation role, but non-core relative to the
catalytic PI3Kdelta function.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta contributes to mast-cell degranulation, but this is a
cell-type-specific effector output rather than the core molecular function.
supported_by:
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence_type: TAS
original_reference_id: PMID:17290298
review:
summary: Supported PI3K/AKT signaling annotation downstream of PIK3CD-generated
PIP3.
action: ACCEPT
reason: PIP3 produced by p110delta recruits AKT-linked signaling modules. This
pathway term captures the central signaling output of PI3Kdelta even when the
initiating receptor or cell type differs.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: '**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide
3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes
downstream of receptor signaling in immune cells, particularly in lymphocytes.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20940048
supporting_text: PI3Kδ is a lipid kinase of the PI3K class IA family involved in
early signaling events of leukocytes responding to a wide variety of stimuli.
- term:
id: GO:0045087
label: innate immune response
evidence_type: TAS
original_reference_id: PMID:17290298
review:
summary: Supported innate-immune involvement, but this is a broad non-core
immune-system output.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta contributes to myeloid and innate leukocyte activities, but the
precise core function is receptor-linked PIP3 production rather than innate
immunity as a whole.
supported_by:
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- reference_id: PMID:17290298
supporting_text: Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second
messengers that control an array of intracellular signalling pathways that are
known to have important roles in leukocytes.
- term:
id: GO:0045087
label: innate immune response
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported innate-immune involvement, but this is a broad non-core
immune-system output.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta contributes to myeloid and innate leukocyte activities, but the
precise core function is receptor-linked PIP3 production rather than innate
immunity as a whole.
supported_by:
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- reference_id: PMID:17290298
supporting_text: Phosphoinositide 3-kinases (PI3Ks) generate lipid-based second
messengers that control an array of intracellular signalling pathways that are
known to have important roles in leukocytes.
- term:
id: GO:0050852
label: T cell receptor signaling pathway
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported TCR signaling role for PI3Kdelta.
action: ACCEPT
reason: UniProt and the literature synthesis identify p110delta as required for TCR
signaling, making this one of the core immune receptor signaling processes for
PIK3CD.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for T-cell receptor (TCR) signaling.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- term:
id: GO:0050853
label: B cell receptor signaling pathway
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported BCR signaling role for PI3Kdelta.
action: ACCEPT
reason: p110delta is required for BCR signaling and B-cell functional outputs; this
is one of the strongest process annotations for PIK3CD.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: Required for B-cell receptor (BCR) signaling.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- reference_id: PMID:20200404
supporting_text: Thus, we provide novel evidence that p110gamma and p110delta have
overlapping and cell-extrinsic roles in the development, peripheral maintenance,
and function of B cells.
- term:
id: GO:0060374
label: mast cell differentiation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported mast-cell differentiation role, but non-core relative to the
catalytic PI3Kdelta function.
action: KEEP_AS_NON_CORE
reason: Mast-cell maturation/differentiation is a supported leukocyte-cell output of
PI3Kdelta signaling, not the core molecular activity.
supported_by:
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0072672
label: neutrophil extravasation
evidence_type: TAS
original_reference_id: PMID:20940048
review:
summary: Supported leukocyte migration/chemotaxis/extravasation role, but non-core
relative to receptor-proximal PI3Kdelta signaling.
action: KEEP_AS_NON_CORE
reason: PI3Kdelta affects migration of multiple leukocyte types, but these are
cell-type-specific outputs of the core PIP3-generating immune signaling function.
supported_by:
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- reference_id: PMID:20940048
supporting_text: The role of PI3Kδ in myeloid cell activities, such as
inflammation driven cell infiltration, neutrophil oxidative burst, immune
complex mediated macrophage activation, as well as mast cell maturation and
degranulation, has been well illustrated in various studies.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IMP
original_reference_id: PMID:22079609
review:
summary: Over-annotation to positive regulation of gene expression. The available
PIK3CD evidence supports upstream PI3K/AKT signaling more directly than this
distal transcriptional-output term.
action: MARK_AS_OVER_ANNOTATED
reason: Gene-expression changes can occur downstream of PI3K/AKT/FOXO signaling, but
the evidence supports this as a distal pathway output requiring careful
attribution rather than a direct core PIK3CD function. This broad distal term
should not be retained as a core annotation.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Many downstream readouts (e.g., pAKT, pS6) are not
isoform-specific, and class I PI3Ks share overlapping functions; p110δ is
leukocyte-enriched but not exclusively expressed, so immune-context evidence is
strongest for PIK3CD-specific BP claims.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: It highlights pathway antagonism by PTEN/SHIP and connects
FOXO-regulated transcription (e.g., immune differentiation programs) to PI3K
signaling outputs (useful for downstream BP annotations, but requires careful
evidence attribution if annotating those distal effects).
- term:
id: GO:0030335
label: positive regulation of cell migration
evidence_type: IMP
original_reference_id: PMID:22079609
review:
summary: Supported cell-migration role in specific leukocyte and glioma contexts,
but non-core relative to lipid kinase signaling.
action: KEEP_AS_NON_CORE
reason: PIK3CD knockdown decreases glioma-cell migration and PI3Kdelta also affects
leukocyte migration; these are downstream context-specific outputs rather than the
core function.
supported_by:
- reference_id: PMID:22079609
supporting_text: Interestingly, knockdown of p110δ decreased the cell migration
and invasion ability of all GBM cell lines tested.
- reference_id: PMID:20940048
supporting_text: PI3Kδ participates in the development, activation and migration
of T cells and NK cells.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1676048
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-1676109
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9012657
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9021627
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9027275
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9606887
review:
summary: Supported cytoplasmic or cytosolic localization, but this is the
resting/general pool rather than the most informative activated signaling site.
action: KEEP_AS_NON_CORE
reason: UniProt records cytoplasmic localization and the deep research report
describes resting p110delta-p85 complexes as cytosolic. The functionally decisive
event is receptor-driven membrane recruitment, so cytoplasm/cytosol should not be
treated as the core location.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22020336}.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2045911
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2076220
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2316434
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2400009
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-388830
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-388832
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389158
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-508247
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-879917
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8854905
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-912627
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-914182
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9606887
review:
summary: Supported core activated-site localization. PI3Kdelta is recruited to
plasma-membrane receptor/adaptor complexes where its phosphoinositide substrates
reside.
action: ACCEPT
reason: Membrane recruitment is central to class IA PI3Kdelta activity because PIP2
substrate is membrane localized and receptor phosphotyrosine signals recruit the
p85-p110delta complex to the plasma membrane.
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Upon receptor phosphotyrosine signaling, SH2-containing p85
recruits the p85-p110δ complex to the plasma membrane where phosphoinositide
substrates reside.
- reference_id: Reactome:R-HSA-1676048
supporting_text: At the plasma membrane, phosphatidylinositol-4,5-bisphosphate
3-kinase catalytic subunits form complexes with regulatory subunits.
- term:
id: GO:0005942
label: phosphatidylinositol 3-kinase complex
evidence_type: NAS
original_reference_id: PMID:9113989
review:
summary: The complex assignment is valid but should use the more specific class IA
phosphatidylinositol 3-kinase complex term.
action: MODIFY
reason: PIK3CD is not just any PI3K-complex component; it is the p110delta catalytic
subunit of class IA p85-family regulatory complexes. GO:0005943 captures the
correct complex subtype.
proposed_replacement_terms:
- id: GO:0005943
label: phosphatidylinositol 3-kinase complex, class IA
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- term:
id: GO:0005942
label: phosphatidylinositol 3-kinase complex
evidence_type: NAS
original_reference_id: PMID:9235916
review:
summary: The complex assignment is valid but should use the more specific class IA
phosphatidylinositol 3-kinase complex term.
action: MODIFY
reason: PIK3CD is not just any PI3K-complex component; it is the p110delta catalytic
subunit of class IA p85-family regulatory complexes. GO:0005943 captures the
correct complex subtype.
proposed_replacement_terms:
- id: GO:0005943
label: phosphatidylinositol 3-kinase complex, class IA
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: p110δ forms a class IA heterodimer with p85-family regulatory
subunits, with p85 both stabilizing and inhibiting the catalytic subunit in
resting cells.
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- term:
id: GO:0006468
label: protein phosphorylation
evidence_type: NAS
original_reference_id: PMID:9113989
review:
summary: Over-annotation to protein phosphorylation. PIK3CD is primarily a
phosphoinositide lipid kinase, not a protein kinase.
action: MODIFY
reason: PMID:9113989 reports lipid substrate specificity and explicitly
distinguishes p110delta from p110alpha by noting that it does not phosphorylate
p85, despite intrinsic autophosphorylation. The same-aspect replacement should be
lipid phosphorylation rather than general protein phosphorylation; the specific
PI(4,5)P2 3-kinase molecular function is handled separately.
proposed_replacement_terms:
- id: GO:0046834
label: lipid phosphorylation
supported_by:
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- reference_id: PMID:9113989
supporting_text: Unlike p110alpha, p110delta does not phosphorylate p85 but
instead harbors an intrinsic autophosphorylation capacity.
- term:
id: GO:0007165
label: signal transduction
evidence_type: NAS
original_reference_id: PMID:9113989
review:
summary: The generic signal-transduction annotation should be narrowed to PI3K/AKT
and immune receptor signaling.
action: MODIFY
reason: PIK3CD participates in signaling by generating PIP3 downstream of receptor
activation. The generic signal transduction parent obscures the specific PI3K/AKT,
BCR, and TCR pathways supported by the evidence.
proposed_replacement_terms:
- id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
- id: GO:0050853
label: B cell receptor signaling pathway
- id: GO:0050852
label: T cell receptor signaling pathway
supported_by:
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and
related receptor/adaptor systems), framing the major immune-cell BP terms
relevant for PIK3CD.
- term:
id: GO:0016303
label: 1-phosphatidylinositol-3-kinase activity
evidence_type: NAS
original_reference_id: PMID:9235916
review:
summary: Core molecular function as a phosphatidylinositol 3-kinase catalytic
subunit.
action: ACCEPT
reason: This parent PI3K activity term is valid for p110delta, although GO:0046934
is the most specific MF term for its canonical PIP2-to-PIP3 reaction.
supported_by:
- reference_id: PMID:9235916
supporting_text: Recombinant p110delta phosphorylates phosphatidylinositol and
coimmunoprecipitates with p85.
- reference_id: PMID:9113989
supporting_text: p110delta displays a broad phosphoinositide lipid substrate
specificity and interacts with SH2/SH3 domain-containing p85 adaptor proteins
and with GTP-bound Ras.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to
orthologs by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
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: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:17290298
title: 'PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis
and beyond?'
findings: []
- id: PMID:17371229
title: The PI3K p110delta controls T-cell development, differentiation and regulation.
findings: []
- id: PMID:20200404
title: The catalytic PI3K isoforms p110gamma and p110delta contribute to B cell
development and maintenance, transformation, and proliferation.
findings: []
- id: PMID:20940048
title: Phosphoinositide 3-kinase delta (PI3Kδ) in leukocyte signaling and function.
findings: []
- id: PMID:21827948
title: Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and
membranes reveals aspects of regulation distinct from p110α.
findings: []
- id: PMID:22020336
title: p37δ is a new isoform of PI3K p110δ that increases cell proliferation and is
overexpressed in tumors.
findings: []
- id: PMID:22079609
title: The catalytic phosphoinositol 3-kinase isoform p110δ is required for glioma
cell migration and invasion.
findings: []
- id: PMID:24165795
title: Dominant-activating germline mutations in the gene encoding the PI(3)K
catalytic subunit p110δ result in T cell senescence and human immunodeficiency.
findings: []
- id: PMID:25339672
title: Human IgA Fc receptor FcαRI (CD89) triggers different forms of neutrophil death
depending on the inflammatory microenvironment.
findings: []
- id: PMID:27616589
title: PI3Kδ and primary immunodeficiencies.
findings: []
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and disease
networks.
findings: []
- id: PMID:31031754
title: 'Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated
PI3K Delta Syndrome.'
findings: []
- id: PMID:31915155
title: PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32606397
title: PI3K activation is enhanced by FOXM1D binding to p110 and p85 subunits.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
findings: []
- id: PMID:35271311
title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
findings: []
- id: PMID:40205054
title: Multimodal cell maps as a foundation for structural and functional genomics.
findings: []
- id: PMID:9113989
title: P110delta, a novel phosphoinositide 3-kinase in leukocytes.
findings: []
- id: PMID:9235916
title: p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that
associates with p85 and is expressed predominantly in leukocytes.
findings: []
- id: Reactome:R-HSA-1676048
title: PI(4,5)P2 is phosphorylated to PI(3,4,5)P3 by PIK3C[1] at the plasma membrane
findings: []
- id: Reactome:R-HSA-1676109
title: PI4P is phosphorylated to PI(3,4)P2 by PI3K3C[2] at the plasma membrane
findings: []
- id: Reactome:R-HSA-2045911
title: BCAP Signalosome phosphorylates PI(4,5)P2 forming PI(3,4,5)P3
findings: []
- id: Reactome:R-HSA-2076220
title: CD19 Signalosome phosphorylates PI(4,5)P2 forming PI(3,4,5)P3
findings: []
- id: Reactome:R-HSA-2316434
title: PI3K phosphorylates PIP2 to PIP3
findings: []
- id: Reactome:R-HSA-2400009
title: PI3K inhibitors block PI3K catalytic activity
findings: []
- id: Reactome:R-HSA-388830
title: PI3K binds ICOS
findings: []
- id: Reactome:R-HSA-388832
title: PI3K binds CD28
findings: []
- id: Reactome:R-HSA-389158
title: CD28 bound PI3K phosphorylates PIP2 to PIP3
findings: []
- id: Reactome:R-HSA-389356
title: Co-stimulation by CD28
findings: []
- id: Reactome:R-HSA-508247
title: Gab2 binds the p85 subunit of Class 1A PI3 kinases
findings: []
- id: Reactome:R-HSA-879917
title: CBL, GRB2, FYN and PI3K p85 subunit are constitutively associated
findings: []
- id: Reactome:R-HSA-8854905
title: p-5Y-GAB in the RET-GRB2-GAB complexes binds p85-PI3K
findings: []
- id: Reactome:R-HSA-9012657
title: EPO:phospho-EPOR:phospho-JAK2:LYN:phospho-IRS2 binds PI3K
findings: []
- id: Reactome:R-HSA-9021627
title: EPOR-associated PI3K phosphorylates PIP2 to PIP3
findings: []
- id: Reactome:R-HSA-9027275
title: EPO:phospho-EPOR:phospho-JAK2:LYN:IRS2:phospho-GAB1 binds PI3K
findings: []
- id: Reactome:R-HSA-912627
title: CBL ubiquitinates PI3K
findings: []
- id: Reactome:R-HSA-914182
title: 14-3-3 zeta binding allows recruitment of PI3K
findings: []
- id: Reactome:R-HSA-9606887
title: p-CD19:VAV binds PI3K and GRB2
findings: []
- id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
title: Falcon deep research report on PIK3CD
findings: []
- id: file:human/PIK3CD/PIK3CD-uniprot.txt
title: UniProtKB record for PIK3CD
findings: []
core_functions:
- molecular_function:
id: GO:0046934
label: 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
description: PIK3CD/p110delta is the leukocyte-enriched class IA PI3K catalytic
subunit that forms p85-family regulatory complexes and generates PIP3 from PI(4,5)P2
at receptor-activated membranes.
directly_involved_in:
- id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
- id: GO:0050853
label: B cell receptor signaling pathway
- id: GO:0050852
label: T cell receptor signaling pathway
- id: GO:0031295
label: T cell costimulation
locations:
- id: GO:0005886
label: plasma membrane
in_complex:
id: GO:0005943
label: phosphatidylinositol 3-kinase complex, class IA
supported_by:
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: '**PIK3CD** encodes the catalytic subunit **p110δ** of **class IA phosphoinositide
3-kinase (PI3Kδ)**, a lipid kinase that produces **PI(3,4,5)P3 (PIP3)** at membranes
downstream of receptor signaling in immune cells, particularly in lymphocytes.'
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: Class I/IA PI3Ks, including p110δ, phosphorylate PI(4,5)P2 to
PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD.
- reference_id: file:human/PIK3CD/PIK3CD-deep-research-falcon.md
supporting_text: In immune cells, class IA PI3K (including p110δ) propagates
signaling downstream of **BCR, TCR, CD28, ICOS, CD19, BAFF-R, CD40** (and related
receptor/adaptor systems), framing the major immune-cell BP terms relevant for
PIK3CD.
- reference_id: Reactome:R-HSA-389158
supporting_text: Upon binding to CD28, the PI3K enzyme catalyzes the phosphorylation
of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol
3,4,5-trisphosphate (PIP3).
- reference_id: file:human/PIK3CD/PIK3CD-uniprot.txt
supporting_text: ComplexPortal; CPX-5983; Phosphatidylinositol 3-kinase complex
class IA, p110delta/p85alpha.
proposed_new_terms: []
suggested_questions:
- question: Which PIK3CD-dependent leukocyte migration, neutrophil death, and
endothelial angiogenesis annotations remain physiologically relevant in human
primary cells after controlling for class I PI3K isoform redundancy and inhibitor
selectivity?
- question: Should GO include a more specific biological-process term for class I
PI3K-mediated PI(3,4,5)P3 biosynthesis to avoid using PI3P-centered or overly broad
phosphatidylinositol phosphate biosynthetic process terms for PIK3CD?
suggested_experiments:
- description: Use isoform-selective genetic rescue in human primary B and T cells to
separate PIK3CD-specific BCR, TCR, and CD28 signaling outputs from overlapping
PIK3CA/PIK3CB/PIK3CG class I PI3K activity.
experiment_type: primary-cell genetic rescue and phosphoprotein/PIP3 readout
- description: Measure PI(4,5)P2-to-PIP3 and PI4P-to-PI(3,4)P2 product formation for
p110delta-p85 complexes under matched in vitro and membrane-recruitment conditions
to clarify whether PI4P kinase annotations should remain non-core.
experiment_type: lipid kinase substrate-specificity assay