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-p110Ξ΄ 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 p110Ξ΄ decreased the cell migration and invasion ability of all GBM cell lines tested. PMID:20940048 PI3KΞ΄ 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 p110Ξ΄ 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 **p110Ξ΄** of **class IA phosphoinositide 3-kinase (PI3KΞ΄)**, 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 p110Ξ΄) 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 PI3KΞ΄ 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 p110Ξ΄, 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 **p110Ξ΄** of **class IA phosphoinositide 3-kinase (PI3KΞ΄)**, 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 p110Ξ΄) 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-p110Ξ΄ 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 p110Ξ΄, 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 p110Ξ΄, 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 PI3KΞ΄ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3KΞ΄ gleaned from these patients, as well as implications of these findings for clinical therapy. PMID:20940048 As a result of the broad effects of PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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 p110Ξ΄) 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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 PI3KΞ΄ 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 PI3KΞ΄ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3KΞ΄ 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 p110Ξ΄, 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-p110Ξ΄ 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-p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄, 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 The role of PI3KΞ΄ 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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 p110Ξ΄) 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 p110Ξ΄ 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; p110Ξ΄ 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; p110Ξ΄ 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 p110Ξ΄, 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 p110Ξ΄, 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 p110Ξ΄, 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; p110Ξ΄ 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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 PI3KΞ΄ 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; p110Ξ΄ 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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: FcΞ±RI-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 FcΞ±RI-mediated death by additional recruitment of caspase-independent pathways, but this required PI3K class IA and MAPK signaling. PMID:20940048 The role of PI3KΞ΄ 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 **p110Ξ΄** of **class IA phosphoinositide 3-kinase (PI3KΞ΄)**, 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 p110Ξ΄) 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 PI3KΞ΄ 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 PI3KΞ΄ 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 p110Ξ΄, 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 p110Ξ΄, 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; p110Ξ΄ 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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; p110Ξ΄ 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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; p110Ξ΄ 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p37Ξ΄ is a new isoform of PI3K p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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-p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄) 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 p110Ξ΄, 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 PI3KΞ΄ 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 PI3KΞ΄ 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 PI3KΞ΄ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3KΞ΄ 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. |
| GO:0038084 vascular endothelial growth factor signaling pathway | IGI PMID:31915155 PI3KΞ΄ 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 p110Ξ΄ 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; p110Ξ΄ 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 PI3KΞ΄ 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 p110Ξ΄ 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; p110Ξ΄ 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 PI3KΞ΄ 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 p110Ξ΄ 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; p110Ξ΄ 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 PI3KΞ΄ 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 **p110Ξ΄** of **class IA phosphoinositide 3-kinase (PI3KΞ΄)**, 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 p110Ξ΄) 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 PI3KΞ΄ 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 p110Ξ΄ 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; p110Ξ΄ 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 PI3KΞ΄ 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 p110Ξ΄ 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; p110Ξ΄ 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 FcΞ±RI (CD89) triggers different forms ... | KEEP AS NON CORE | Summary: Supported neutrophil-death/apoptotic-process annotation, but non-core and context-dependent. Reason: FcΞ±RI-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 FcΞ±RI-mediated death by additional recruitment of caspase-independent pathways, but this required PI3K class IA and MAPK signaling. PMID:20940048 The role of PI3KΞ΄ 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 FcΞ±RI (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 **p110Ξ΄** of **class IA phosphoinositide 3-kinase (PI3KΞ΄)**, 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 p110Ξ΄) 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 PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ 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 PI3KΞ΄ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3KΞ΄ gleaned from these patients, as well as implications of these findings for clinical therapy. PMID:20940048 As a result of the broad effects of PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ expression or activity leads to decreased inflammatory and immune responses in vivo. |
| GO:0002551 mast cell chemotaxis | TAS PMID:20940048 Phosphoinositide 3-kinase delta (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 The role of PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ expression or activity leads to decreased inflammatory and immune responses in vivo. |
| GO:0006954 inflammatory response | TAS PMID:20940048 Phosphoinositide 3-kinase delta (PI3KΞ΄) 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 PI3KΞ΄ in leukocyte functions, the disruption of PI3KΞ΄ expression or activity leads to decreased inflammatory and immune responses in vivo. |
| GO:0010818 T cell chemotaxis | TAS PMID:20940048 Phosphoinositide 3-kinase delta (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 The role of PI3KΞ΄ 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 p110Ξ΄, 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 (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. |
| GO:0030593 neutrophil chemotaxis | TAS PMID:20940048 Phosphoinositide 3-kinase delta (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 The role of PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 The role of PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 The role of PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ 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 (PI3KΞ΄) 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 (PI3KΞ΄) 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 PI3KΞ΄ 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 **p110Ξ΄** of **class IA phosphoinositide 3-kinase (PI3KΞ΄)**, 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 p110Ξ΄) 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 PI3KΞ΄ 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 PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ 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 (PI3KΞ΄) 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 p110Ξ΄) 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 PI3KΞ΄ 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 (PI3KΞ΄) 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 p110Ξ΄) 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 (PI3KΞ΄) 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 PI3KΞ΄ 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 (PI3KΞ΄) 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 PI3KΞ΄ participates in the development, activation and migration of T cells and NK cells. PMID:20940048 The role of PI3KΞ΄ 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 p110Ξ΄ 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; p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ decreased the cell migration and invasion ability of all GBM cell lines tested. PMID:20940048 PI3KΞ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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-p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄ 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 p110Ξ΄) 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 p110Ξ΄, phosphorylate PI(4,5)P2 to PI(3,4,5)P3; this is the core enzymatic activity of PIK3CD. |
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Download this section (compressed HTML)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
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