INPP5D encodes SHIP1, an SH2-domain-containing inositol/phosphatidylinositol 5-phosphatase expressed mainly in immune and hematopoietic cells. SHIP1 hydrolyzes PtdIns(3,4,5)P3 to PtdIns(3,4)P2 and also acts on soluble inositol polyphosphates, thereby limiting PI3K-dependent signaling from B-cell, Fc, cytokine, NK-cell, T-cell, myeloid, and other immune receptors. Through its SH2 domain, SHIP1 is recruited to phosphorylated inhibitory receptor/adaptor motifs at cytosolic, membrane, membrane-raft, and cytoskeletal signaling sites, where it helps terminate receptor signaling, restrain immune-cell activation, regulate myeloid and lymphoid cell behavior, and modulate phagocytosis, chemotaxis, cytotoxicity, mast-cell responses, and osteoclast-related pathways.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0050776 regulation of immune response | IBA GO_REF:0000033 | ACCEPT | Summary: SHIP1 attenuates immune-receptor signaling by dephosphorylating PIP3 and by recruitment to phosphorylated inhibitory receptor motifs. Reason: Retain as core or near-core immune signaling biology because SHIP1 is a central negative regulator of PI3K-linked B-cell, myeloid, NK-cell, and other hematopoietic receptor pathways. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0009968 negative regulation of signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: SHIP1 attenuates immune-receptor signaling by dephosphorylating PIP3 and by recruitment to phosphorylated inhibitory receptor motifs. Reason: Retain as core or near-core immune signaling biology because SHIP1 is a central negative regulator of PI3K-linked B-cell, myeloid, NK-cell, and other hematopoietic receptor pathways. |
| GO:0045579 positive regulation of B cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: This immune differentiation or effector outcome is plausible for SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase mechanism. Reason: Keep as non-core because the annotation reflects a cell-type-specific developmental or effector outcome of SHIP1 immune signaling rather than the defining catalytic/receptor-proximal molecular function. |
| GO:0045659 negative regulation of neutrophil differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: This immune differentiation or effector outcome is plausible for SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase mechanism. Reason: Keep as non-core because the annotation reflects a cell-type-specific developmental or effector outcome of SHIP1 immune signaling rather than the defining catalytic/receptor-proximal molecular function. |
| GO:0045779 negative regulation of bone resorption | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: This immune differentiation or effector outcome is plausible for SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase mechanism. Reason: Keep as non-core because the annotation reflects a cell-type-specific developmental or effector outcome of SHIP1 immune signaling rather than the defining catalytic/receptor-proximal molecular function. |
| GO:0004439 phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0004445 inositol-polyphosphate 5-phosphatase activity | IEA GO_REF:0000003 | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0006661 phosphatidylinositol biosynthetic process | IEA GO_REF:0000117 | MODIFY | Summary: SHIP1 dephosphorylates phosphoinositides; biosynthetic process is the wrong direction for this enzymatic activity. Reason: Replace phosphatidylinositol biosynthetic process with phosphatidylinositol dephosphorylation for INPP5D phosphatase biology. Proposed replacements: phosphatidylinositol dephosphorylation |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0016791 phosphatase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic phosphatase activity is too broad for a lipid/inositol polyphosphate 5-phosphatase. Reason: Replace broad phosphatase activity with the specific SHIP1 PIP3 and inositol-polyphosphate 5-phosphatase activities. |
| GO:0034485 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0045121 membrane raft | IEA GO_REF:0000044 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0046856 phosphatidylinositol dephosphorylation | IEA GO_REF:0000002 | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0052658 inositol-1,4,5-trisphosphate 5-phosphatase activity | IEA GO_REF:0000116 | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0052659 inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity | IEA GO_REF:0000116 | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0005515 protein binding | IPI PMID:10382761 Fcgamma receptor-mediated inhibition of human B cell activat... | MODIFY | Summary: The interaction evidence supports SHIP1 recruitment to phosphorylated receptor or adaptor motifs, but generic protein binding is too broad. Reason: Replace generic protein binding with phosphotyrosine residue binding, which better captures SHIP1 SH2-domain recruitment to phosphorylated ITIM/ITSM or related motifs. Proposed replacements: phosphotyrosine residue binding |
| GO:0005515 protein binding | IPI PMID:15090612 CIN85 associates with multiple effectors controlling intrace... | MARK AS OVER ANNOTATED | Summary: The cited interaction is not a defining SHIP1 molecular function and generic protein binding is not informative for curation. Reason: Mark as over-annotated because this generic interaction-map or accessory-protein evidence does not define the core SHIP1 catalytic or receptor-proximal immune signaling function. |
| GO:0005515 protein binding | IPI PMID:24642916 Fine specificity and molecular competition in SLAM family re... | MODIFY | Summary: The interaction evidence supports SHIP1 recruitment to phosphorylated receptor or adaptor motifs, but generic protein binding is too broad. Reason: Replace generic protein binding with phosphotyrosine residue binding, which better captures SHIP1 SH2-domain recruitment to phosphorylated ITIM/ITSM or related motifs. Proposed replacements: phosphotyrosine residue binding |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: The cited interaction is not a defining SHIP1 molecular function and generic protein binding is not informative for curation. Reason: Mark as over-annotated because this generic interaction-map or accessory-protein evidence does not define the core SHIP1 catalytic or receptor-proximal immune signaling function. |
| GO:0005515 protein binding | IPI PMID:26221972 A polymorphism in a phosphotyrosine signalling motif of CD22... | MODIFY | Summary: The interaction evidence supports SHIP1 recruitment to phosphorylated receptor or adaptor motifs, but generic protein binding is too broad. Reason: Replace generic protein binding with phosphotyrosine residue binding, which better captures SHIP1 SH2-domain recruitment to phosphorylated ITIM/ITSM or related motifs. Proposed replacements: phosphotyrosine residue binding |
| GO:0005515 protein binding | IPI PMID:9148918 A novel phosphotyrosine motif with a critical amino acid at ... | UNDECIDED | Summary: The cached abstract is about SHP-1 phosphotyrosine-motif binding and does not expose SHIP1-specific evidence. Reason: Use UNDECIDED rather than REMOVE because this is an experimental interaction annotation but the abstract-only cache does not show the SHIP1-specific evidence that curators may have used. |
| GO:0006661 phosphatidylinositol biosynthetic process | TAS Reactome:R-HSA-1660499 | MODIFY | Summary: Reactome captures PIP pathway chemistry, but biosynthetic process is the wrong direction for INPP5D. Reason: Replace phosphatidylinositol biosynthetic process with phosphatidylinositol dephosphorylation for SHIP1 5-phosphatase activity. Proposed replacements: phosphatidylinositol dephosphorylation |
| GO:0050852 T cell receptor signaling pathway | TAS Reactome:R-HSA-202403 | KEEP AS NON CORE | Summary: This immune differentiation or effector outcome is plausible for SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase mechanism. Reason: Keep as non-core because the annotation reflects a cell-type-specific developmental or effector outcome of SHIP1 immune signaling rather than the defining catalytic/receptor-proximal molecular function. |
| GO:0016314 phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity | TAS Reactome:R-HSA-202237 | MODIFY | Summary: INPP5D hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3, not the 3-phosphate. Reason: Replace the 3-phosphatase term with phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity, which matches SHIP1 chemistry. Proposed replacements: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity |
| GO:0034485 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | TAS Reactome:R-HSA-1675949 | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0004439 phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity | EXP PMID:10764818 The isolation and characterization of a cDNA encoding phosph... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0016020 membrane | EXP PMID:10822173 The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 a... | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0034485 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | EXP PMID:10764818 The isolation and characterization of a cDNA encoding phosph... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0034485 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | EXP PMID:8723348 Multiple forms of an inositol polyphosphate 5-phosphatase fo... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0034485 phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity | EXP PMID:8769125 Cloning and expression of a human placenta inositol 1,3,4,5-... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0045121 membrane raft | ISS GO_REF:0000024 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0052659 inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity | EXP PMID:8769125 Cloning and expression of a human placenta inositol 1,3,4,5-... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0052659 inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity | EXP PMID:9108392 Purification and molecular cloning of SH2- and SH3-containin... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0004445 inositol-polyphosphate 5-phosphatase activity | IDA PMID:10764818 The isolation and characterization of a cDNA encoding phosph... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0005737 cytoplasm | IDA PMID:10822173 The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 a... | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0045953 negative regulation of natural killer cell mediated cytotoxicity | IDA PMID:23154388 Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT... | ACCEPT | Summary: SHIP1 attenuates immune-receptor signaling by dephosphorylating PIP3 and by recruitment to phosphorylated inhibitory receptor motifs. Reason: Retain as core or near-core immune signaling biology because SHIP1 is a central negative regulator of PI3K-linked B-cell, myeloid, NK-cell, and other hematopoietic receptor pathways. |
| GO:0005515 protein binding | IPI PMID:9485206 Inhibition of antigen-induced T cell response and antibody-i... | REMOVE | Summary: The cached abstract explicitly reports NKG2A association with SHP-1 and SHP-2 but not with SHIP. Reason: Remove because the cited abstract directly contradicts a SHIP1/NKG2A interaction: it states that NKG2A phospho-ITIMs associated with SHP-1/SHP-2, but not SHIP. |
| GO:0005515 protein binding | IPI PMID:19843936 FCRL3, an autoimmune susceptibility gene, has inhibitory pot... | MODIFY | Summary: The interaction evidence supports SHIP1 recruitment to phosphorylated receptor or adaptor motifs, but generic protein binding is too broad. Reason: Replace generic protein binding with phosphotyrosine residue binding, which better captures SHIP1 SH2-domain recruitment to phosphorylated ITIM/ITSM or related motifs. Proposed replacements: phosphotyrosine residue binding |
| GO:0005515 protein binding | IPI PMID:20933011 FCRL6 receptor: expression and associated proteins. | MODIFY | Summary: The interaction evidence supports SHIP1 recruitment to phosphorylated receptor or adaptor motifs, but generic protein binding is too broad. Reason: Replace generic protein binding with phosphotyrosine residue binding, which better captures SHIP1 SH2-domain recruitment to phosphorylated ITIM/ITSM or related motifs. Proposed replacements: phosphotyrosine residue binding |
| GO:0005515 protein binding | IPI PMID:26755705 Identification of CD112R as a novel checkpoint for human T c... | MODIFY | Summary: The interaction evidence supports SHIP1 recruitment to phosphorylated receptor or adaptor motifs, but generic protein binding is too broad. Reason: Replace generic protein binding with phosphotyrosine residue binding, which better captures SHIP1 SH2-domain recruitment to phosphorylated ITIM/ITSM or related motifs. Proposed replacements: phosphotyrosine residue binding |
| GO:0005515 protein binding | IPI PMID:16339535 The inhibitory receptor IRp60 (CD300a) is expressed and func... | UNDECIDED | Summary: The cached abstract reports inhibitory receptor phosphatase recruitment in mast cells but does not name SHIP1 specifically. Reason: Use UNDECIDED because the annotation is experimental but the abstract-only cached evidence does not verify an INPP5D/SHIP1 interaction. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1675949 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1855218 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202237 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-210290 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-913374 | ACCEPT | Summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and cytoskeletal/plasma-membrane signaling sites after immune-receptor activation. Reason: Retain because SHIP1 functions from cytosolic pools that translocate to membrane and membrane-raft receptor-signaling sites, with cytoskeleton/membrane ruffle context reported by UniProt and orthology-supported annotations. |
| GO:0005515 protein binding | IPI PMID:21712384 Silencer of death domains (SODD) inhibits skeletal muscle an... | MARK AS OVER ANNOTATED | Summary: The cited interaction is not a defining SHIP1 molecular function and generic protein binding is not informative for curation. Reason: Mark as over-annotated because this generic interaction-map or accessory-protein evidence does not define the core SHIP1 catalytic or receptor-proximal immune signaling function. |
| GO:0004445 inositol-polyphosphate 5-phosphatase activity | TAS PMID:8769125 Cloning and expression of a human placenta inositol 1,3,4,5-... | ACCEPT | Summary: SHIP1/INPP5D is a hematopoietic inositol/phosphatidylinositol 5-phosphatase, with core activity toward PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. Reason: Retain as core because INPP5D/SHIP1 enzymatically removes 5-phosphate groups from PtdIns(3,4,5)P3 and soluble inositol polyphosphates, thereby controlling PI3K-linked signaling in immune and hematopoietic cells. |
| GO:0006796 phosphate-containing compound metabolic process | TAS PMID:8769125 Cloning and expression of a human placenta inositol 1,3,4,5-... | MODIFY | Summary: Phosphate-containing compound metabolic process is far too broad for the enzymatic evidence. Reason: Replace the broad metabolic process term with specific phosphatidylinositol dephosphorylation and 5-phosphatase activities. |
| GO:0007165 signal transduction | TAS PMID:8769125 Cloning and expression of a human placenta inositol 1,3,4,5-... | MODIFY | Summary: Broad signal transduction is less informative than SHIP1 negative regulation of PI3K-linked immune signaling. Reason: Replace broad signal transduction with negative regulation of signal transduction driven by SHIP1 5-phosphatase activity. Proposed replacements: negative regulation of signal transduction |
| GO:0001784 phosphotyrosine residue binding | IPI PMID:23154388 Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT... | NEW | Summary: SHIP1 is recruited through its SH2 domain to phosphorylated inhibitory receptor motifs, coupling phosphotyrosine recognition to immune signal attenuation. Reason: Multiple generic protein-binding annotations actually describe phosphotyrosine-dependent SHIP1 recruitment to inhibitory receptor/adaptor motifs; GO:0001784 captures that molecular function more precisely. Supporting Evidence: PMID:23154388 SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated killing inhibition PMID:19843936 SHIP with the ITIM-like motif at 662 PMID:26755705 SHIP was strongly associated with CD112R |
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Download this section (compressed HTML)Q: Should INPP5D/SHIP1 phosphotyrosine-dependent SH2 recruitment be curated broadly as phosphotyrosine residue binding for inhibitory receptor motifs, or split by receptor family context?
Suggested experts: GO molecular-function curators, Immune receptor signaling experts
Q: Which immune effector outcomes should be treated as core for SHIP1 across hematopoietic cells versus retained as cell-type-specific downstream consequences?
Suggested experts: Hematopoietic signaling experts, GO immune process curators
Q: How should Alzheimer/microglial relevance for INPP5D be represented without over-annotating disease progression mechanisms as core molecular function?
Suggested experts: Microglial biology experts, Alzheimer disease genetics curators
Experiment: Use catalytically inactive and SH2-binding-defective INPP5D rescue constructs in primary human macrophages, microglia-like cells, B cells, and NK cells, then measure PtdIns(3,4,5)P3/PtdIns(3,4)P2 dynamics, receptor phosphorylation, Akt/MAPK output, cytokines, phagocytosis, chemotaxis, and cytotoxicity.
Hypothesis: SHIP1 immune-receptor functions require both catalytic PIP3 5-phosphatase activity and SH2-mediated recruitment to phosphorylated inhibitory motifs, with cell-type-specific effector outcomes downstream.
Type: domain-resolved immune signaling rescue assay
Experiment: Compare INPP5D perturbation in human iPSC-derived microglia across basal, TREM2-ligand, Fc-receptor, and amyloid challenge conditions, quantifying phosphoinositide lipids, receptor-proximal signaling, phagocytosis, lipid handling, inflammatory gene expression, and survival.
Hypothesis: Alzheimer-associated INPP5D effects in microglia reflect altered PI3K-lipid signaling thresholds rather than a distinct disease-specific molecular function.
Type: microglial phosphoinositide signaling perturbation assay
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