INPP5D

Existing Annotations Review

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. Proposed replacements: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity inositol-polyphosphate 5-phosphatase activity
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. Proposed replacements: phosphatidylinositol dephosphorylation phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity inositol-polyphosphate 5-phosphatase activity
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

📄 View Raw YAML

id: Q92835
gene_symbol: INPP5D
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: '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.'
alternative_products:
- name: '1'
  id: Q92835-1
- name: '2'
  id: Q92835-2
  sequence_note: VSP_027978
- name: 3 (SIP-110)
  id: Q92835-3
  sequence_note: VSP_027977, VSP_027979
existing_annotations:
- term:
    id: GO:0050776
    label: regulation of immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SHIP1 attenuates immune-receptor signaling by dephosphorylating 
      PIP3 and by recruitment to phosphorylated inhibitory receptor motifs.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0009968
    label: negative regulation of signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SHIP1 attenuates immune-receptor signaling by dephosphorylating 
      PIP3 and by recruitment to phosphorylated inhibitory receptor motifs.
    action: ACCEPT
    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.
- term:
    id: GO:0045579
    label: positive regulation of B cell differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This immune differentiation or effector outcome is plausible for 
      SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase 
      mechanism.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0045659
    label: negative regulation of neutrophil differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This immune differentiation or effector outcome is plausible for 
      SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase 
      mechanism.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0045779
    label: negative regulation of bone resorption
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: This immune differentiation or effector outcome is plausible for 
      SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase 
      mechanism.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0004439
    label: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0004445
    label: inositol-polyphosphate 5-phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0006661
    label: phosphatidylinositol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: SHIP1 dephosphorylates phosphoinositides; biosynthetic process is 
      the wrong direction for this enzymatic activity.
    action: MODIFY
    reason: Replace phosphatidylinositol biosynthetic process with 
      phosphatidylinositol dephosphorylation for INPP5D phosphatase biology.
    proposed_replacement_terms:
    - id: GO:0046856
      label: phosphatidylinositol dephosphorylation
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0016791
    label: phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic phosphatase activity is too broad for a lipid/inositol 
      polyphosphate 5-phosphatase.
    action: MODIFY
    reason: Replace broad phosphatase activity with the specific SHIP1 PIP3 and 
      inositol-polyphosphate 5-phosphatase activities.
    proposed_replacement_terms:
    - id: GO:0034485
      label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
    - id: GO:0004445
      label: inositol-polyphosphate 5-phosphatase activity
- term:
    id: GO:0034485
    label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0046856
    label: phosphatidylinositol dephosphorylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0052658
    label: inositol-1,4,5-trisphosphate 5-phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0052659
    label: inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10382761
  qualifier: enables
  review:
    summary: The interaction evidence supports SHIP1 recruitment to 
      phosphorylated receptor or adaptor motifs, but generic protein binding is 
      too broad.
    action: MODIFY
    reason: Replace generic protein binding with phosphotyrosine residue 
      binding, which better captures SHIP1 SH2-domain recruitment to 
      phosphorylated ITIM/ITSM or related motifs.
    proposed_replacement_terms:
    - id: GO:0001784
      label: phosphotyrosine residue binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15090612
  qualifier: enables
  review:
    summary: The cited interaction is not a defining SHIP1 molecular function 
      and generic protein binding is not informative for curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24642916
  qualifier: enables
  review:
    summary: The interaction evidence supports SHIP1 recruitment to 
      phosphorylated receptor or adaptor motifs, but generic protein binding is 
      too broad.
    action: MODIFY
    reason: Replace generic protein binding with phosphotyrosine residue 
      binding, which better captures SHIP1 SH2-domain recruitment to 
      phosphorylated ITIM/ITSM or related motifs.
    proposed_replacement_terms:
    - id: GO:0001784
      label: phosphotyrosine residue binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: The cited interaction is not a defining SHIP1 molecular function 
      and generic protein binding is not informative for curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26221972
  qualifier: enables
  review:
    summary: The interaction evidence supports SHIP1 recruitment to 
      phosphorylated receptor or adaptor motifs, but generic protein binding is 
      too broad.
    action: MODIFY
    reason: Replace generic protein binding with phosphotyrosine residue 
      binding, which better captures SHIP1 SH2-domain recruitment to 
      phosphorylated ITIM/ITSM or related motifs.
    proposed_replacement_terms:
    - id: GO:0001784
      label: phosphotyrosine residue binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9148918
  qualifier: enables
  review:
    summary: The cached abstract is about SHP-1 phosphotyrosine-motif binding 
      and does not expose SHIP1-specific evidence.
    action: UNDECIDED
    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.
- term:
    id: GO:0006661
    label: phosphatidylinositol biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1660499
  qualifier: involved_in
  review:
    summary: Reactome captures PIP pathway chemistry, but biosynthetic process 
      is the wrong direction for INPP5D.
    action: MODIFY
    reason: Replace phosphatidylinositol biosynthetic process with 
      phosphatidylinositol dephosphorylation for SHIP1 5-phosphatase activity.
    proposed_replacement_terms:
    - id: GO:0046856
      label: phosphatidylinositol dephosphorylation
- term:
    id: GO:0050852
    label: T cell receptor signaling pathway
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202403
  qualifier: involved_in
  review:
    summary: This immune differentiation or effector outcome is plausible for 
      SHIP1 signaling but is downstream of the core PIP3/IP4 phosphatase 
      mechanism.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0016314
    label: phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202237
  qualifier: enables
  review:
    summary: INPP5D hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3, not the 
      3-phosphate.
    action: MODIFY
    reason: Replace the 3-phosphatase term with 
      phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity, which 
      matches SHIP1 chemistry.
    proposed_replacement_terms:
    - id: GO:0034485
      label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
- term:
    id: GO:0034485
    label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1675949
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0004439
    label: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:10764818
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: EXP
  original_reference_id: PMID:10822173
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0034485
    label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:10764818
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0034485
    label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:8723348
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0034485
    label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:8769125
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0052659
    label: inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:8769125
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0052659
    label: inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity
  evidence_type: EXP
  original_reference_id: PMID:9108392
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0004445
    label: inositol-polyphosphate 5-phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:10764818
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10822173
  qualifier: is_active_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0045953
    label: negative regulation of natural killer cell mediated cytotoxicity
  evidence_type: IDA
  original_reference_id: PMID:23154388
  qualifier: involved_in
  review:
    summary: SHIP1 attenuates immune-receptor signaling by dephosphorylating 
      PIP3 and by recruitment to phosphorylated inhibitory receptor motifs.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9485206
  qualifier: enables
  review:
    summary: The cached abstract explicitly reports NKG2A association with SHP-1
      and SHP-2 but not with SHIP.
    action: REMOVE
    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.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19843936
  qualifier: enables
  review:
    summary: The interaction evidence supports SHIP1 recruitment to 
      phosphorylated receptor or adaptor motifs, but generic protein binding is 
      too broad.
    action: MODIFY
    reason: Replace generic protein binding with phosphotyrosine residue 
      binding, which better captures SHIP1 SH2-domain recruitment to 
      phosphorylated ITIM/ITSM or related motifs.
    proposed_replacement_terms:
    - id: GO:0001784
      label: phosphotyrosine residue binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20933011
  qualifier: enables
  review:
    summary: The interaction evidence supports SHIP1 recruitment to 
      phosphorylated receptor or adaptor motifs, but generic protein binding is 
      too broad.
    action: MODIFY
    reason: Replace generic protein binding with phosphotyrosine residue 
      binding, which better captures SHIP1 SH2-domain recruitment to 
      phosphorylated ITIM/ITSM or related motifs.
    proposed_replacement_terms:
    - id: GO:0001784
      label: phosphotyrosine residue binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26755705
  qualifier: enables
  review:
    summary: The interaction evidence supports SHIP1 recruitment to 
      phosphorylated receptor or adaptor motifs, but generic protein binding is 
      too broad.
    action: MODIFY
    reason: Replace generic protein binding with phosphotyrosine residue 
      binding, which better captures SHIP1 SH2-domain recruitment to 
      phosphorylated ITIM/ITSM or related motifs.
    proposed_replacement_terms:
    - id: GO:0001784
      label: phosphotyrosine residue binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16339535
  qualifier: enables
  review:
    summary: The cached abstract reports inhibitory receptor phosphatase 
      recruitment in mast cells but does not name SHIP1 specifically.
    action: UNDECIDED
    reason: Use UNDECIDED because the annotation is experimental but the 
      abstract-only cached evidence does not verify an INPP5D/SHIP1 interaction.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1675949
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1855218
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202237
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-210290
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-913374
  qualifier: located_in
  review:
    summary: SHIP1 is cytosolic and recruited to membranes, membrane rafts, and 
      cytoskeletal/plasma-membrane signaling sites after immune-receptor 
      activation.
    action: ACCEPT
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21712384
  qualifier: enables
  review:
    summary: The cited interaction is not a defining SHIP1 molecular function 
      and generic protein binding is not informative for curation.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0004445
    label: inositol-polyphosphate 5-phosphatase activity
  evidence_type: TAS
  original_reference_id: PMID:8769125
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0006796
    label: phosphate-containing compound metabolic process
  evidence_type: TAS
  original_reference_id: PMID:8769125
  qualifier: involved_in
  review:
    summary: Phosphate-containing compound metabolic process is far too broad 
      for the enzymatic evidence.
    action: MODIFY
    reason: Replace the broad metabolic process term with specific 
      phosphatidylinositol dephosphorylation and 5-phosphatase activities.
    proposed_replacement_terms:
    - id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    - id: GO:0034485
      label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
    - id: GO:0004445
      label: inositol-polyphosphate 5-phosphatase activity
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: TAS
  original_reference_id: PMID:8769125
  qualifier: involved_in
  review:
    summary: Broad signal transduction is less informative than SHIP1 negative 
      regulation of PI3K-linked immune signaling.
    action: MODIFY
    reason: Replace broad signal transduction with negative regulation of signal
      transduction driven by SHIP1 5-phosphatase activity.
    proposed_replacement_terms:
    - id: GO:0009968
      label: negative regulation of signal transduction
- term:
    id: GO:0001784
    label: phosphotyrosine residue binding
  evidence_type: IPI
  original_reference_id: PMID:23154388
  qualifier: enables
  review:
    summary: SHIP1 is recruited through its SH2 domain to phosphorylated 
      inhibitory receptor motifs, coupling phosphotyrosine recognition to immune
      signal attenuation.
    action: NEW
    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.
    additional_reference_ids:
    - PMID:19843936
    - PMID:20933011
    - PMID:26755705
    supported_by:
    - reference_id: PMID:23154388
      supporting_text: SHIP1 silencing can dramatically abolish 
        TIGIT/PVR-mediated killing inhibition
    - reference_id: PMID:19843936
      supporting_text: SHIP with the ITIM-like motif at 662
    - reference_id: PMID:26755705
      supporting_text: SHIP was strongly associated with CD112R
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to
    orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10382761
  title: 'Fcgamma receptor-mediated inhibition of human B cell activation: the role
    of SHP-2 phosphatase.'
  findings: []
- id: PMID:10764818
  title: The isolation and characterization of a cDNA encoding 
    phospholipid-specific inositol polyphosphate 5-phosphatase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Primarily type IV 5-phosphatase paper, but includes direct 
      comparison showing SHIP can hydrolyze PtdIns(4,5)P2 under assay 
      conditions.
- id: PMID:10822173
  title: The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates 
    with the dok1 phosphoprotein in bcr-Abl transformed cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports cytosolic SHIP1/Dok1 complexes and membrane/cytoplasm
      localization context in hematopoietic cells.
- id: PMID:15090612
  title: CIN85 associates with multiple effectors controlling intracellular 
    trafficking of epidermal growth factor receptors.
  findings: []
- id: PMID:16339535
  title: The inhibitory receptor IRp60 (CD300a) is expressed and functional on 
    human mast cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Abstract-only mast-cell inhibitory receptor paper does not 
      name SHIP1; corresponding interaction annotation left UNDECIDED.
- id: PMID:19843936
  title: FCRL3, an autoimmune susceptibility gene, has inhibitory potential on 
    B-cell receptor-mediated signaling.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: FCRL3 inhibitory receptor paper supporting SHIP recruitment to
      an ITIM-like phosphotyrosine motif in BCR signaling context.
- id: PMID:20933011
  title: 'FCRL6 receptor: expression and associated proteins.'
  findings: []
- id: PMID:21712384
  title: Silencer of death domains (SODD) inhibits skeletal muscle and kidney 
    enriched inositol 5-phosphatase (SKIP) and regulates phosphoinositide 
    3-kinase (PI3K)/Akt signaling to the actin cytoskeleton.
  findings: []
- id: PMID:23154388
  title: Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses
    granule polarization and cytotoxicity of NK cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct functional evidence that TIGIT recruits SHIP1 through 
      negative signaling and SHIP1 silencing reverses NK killing inhibition.
- id: PMID:24642916
  title: Fine specificity and molecular competition in SLAM family receptor 
    signalling.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome resource; useful context but 
      generic protein binding is not core SHIP1 function.
- id: PMID:26221972
  title: A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9, 
    SLAMF3) alters SH2 domain binding and T-cell activation.
  findings: []
- id: PMID:26755705
  title: Identification of CD112R as a novel checkpoint for human T cells.
  findings: []
- id: PMID:8723348
  title: Multiple forms of an inositol polyphosphate 5-phosphatase form 
    signaling complexes with Shc and Grb2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary evidence for SIP/SHIP isoforms, Shc/Grb2 complexes, 
      PIP3/IP4 hydrolysis, and PI3K pathway linkage.
- id: PMID:8769125
  title: Cloning and expression of a human placenta inositol 
    1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate 
    5-phosphatase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary cloning/catalytic evidence for INPP5D/hp51CN PIP3 and 
      IP4 5-phosphatase activity.
- id: PMID:9108392
  title: Purification and molecular cloning of SH2- and SH3-containing inositol 
    polyphosphate-5-phosphatase, which is involved in the signaling pathway of 
    granulocyte-macrophage colony-stimulating factor, erythropoietin, and 
    Bcr-Abl.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary evidence for SH2/SH3-containing inositol polyphosphate
      5-phosphatase activity and hematopoietic signaling complexes.
- id: PMID:9148918
  title: A novel phosphotyrosine motif with a critical amino acid at position -2
    for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1.
  findings: []
- id: PMID:9485206
  title: 'Inhibition of antigen-induced T cell response and antibody-induced NK cell
    cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-tyrosine
    phosphatases.'
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: Abstract explicitly says NKG2A phospho-ITIMs associate with 
      SHP-1/SHP-2 but not SHIP; corresponding protein-binding annotation 
      removed.
- id: Reactome:R-HSA-1660499
  title: Synthesis of PIPs at the plasma membrane
  findings: []
- id: Reactome:R-HSA-1675949
  title: PI(3,4,5)P3 is dephosphorylated to PI(3,4)P2 by INPP5[2] at the plasma 
    membrane
  findings: []
- id: Reactome:R-HSA-1855218
  title: I(1,3,4,5)P4 is dephosphorylated to I(1,3,4)P3 by INPP5[3]/ITPK1 in the
    cytosol
  findings: []
- id: Reactome:R-HSA-202237
  title: Hydrolysis of PIP3 to PI(3,4)P2
  findings: []
- id: Reactome:R-HSA-202403
  title: TCR signaling
  findings: []
- id: Reactome:R-HSA-210290
  title: Interaction of PECAM-1 and SHIP
  findings: []
- id: Reactome:R-HSA-913374
  title: Phosphorylated SHC1 recruits SHIP
  findings: []
core_functions:
- molecular_function:
    id: GO:0034485
    label: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
  description: SHIP1 hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 to generate 
    PtdIns(3,4)P2, acting as a receptor-proximal brake on PI3K-dependent 
    signaling in immune and hematopoietic cells.
  directly_involved_in:
  - id: GO:0046856
    label: phosphatidylinositol dephosphorylation
  - id: GO:0009968
    label: negative regulation of signal transduction
  - id: GO:0050776
    label: regulation of immune response
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0045121
    label: membrane raft
  - id: GO:0016020
    label: membrane
  supported_by:
  - reference_id: PMID:8723348
    supporting_text: The SIP proteins hydrolyzed phosphatidylinositol
  - reference_id: PMID:8769125
    supporting_text: PtdIns(3,4,5)P3 hydrolyzing activity
  - reference_id: PMID:23154388
    supporting_text: prematurely terminate phosphatidylinositol 3-kinase (PI3K) 
      and MAPK signaling
- molecular_function:
    id: GO:0004445
    label: inositol-polyphosphate 5-phosphatase activity
  description: SHIP1 also hydrolyzes soluble inositol polyphosphates, especially
    Ins(1,3,4,5)P4, linking its catalytic domain to broader inositol phosphate 
    metabolism in hematopoietic signaling contexts.
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:8769125
    supporting_text: Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3 hydrolyzing activity
  - reference_id: PMID:9108392
    supporting_text: inositol polyphosphate-5-phosphatase activity
- molecular_function:
    id: GO:0001784
    label: phosphotyrosine residue binding
  description: The SHIP1 SH2 domain binds phosphorylated inhibitory 
    receptor/adaptor motifs, recruiting the catalytic enzyme to immune receptor 
    signaling complexes where it attenuates BCR, Fc, TIGIT, SLAM-family, CD112R,
    and related pathways.
  directly_involved_in:
  - id: GO:0009968
    label: negative regulation of signal transduction
  - id: GO:0050776
    label: regulation of immune response
  - id: GO:0045953
    label: negative regulation of natural killer cell mediated cytotoxicity
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0045121
    label: membrane raft
  supported_by:
  - reference_id: PMID:23154388
    supporting_text: SHIP1 silencing can dramatically abolish TIGIT/PVR-mediated
      killing inhibition
  - reference_id: PMID:19843936
    supporting_text: SHIP with the ITIM-like motif at 662
  - reference_id: PMID:26755705
    supporting_text: SHIP was strongly associated with CD112R
proposed_new_terms: []
suggested_questions:
- question: Should INPP5D/SHIP1 phosphotyrosine-dependent SH2 recruitment be 
    curated broadly as phosphotyrosine residue binding for inhibitory receptor 
    motifs, or split by receptor family context?
  experts:
  - GO molecular-function curators
  - Immune receptor signaling experts
- question: Which immune effector outcomes should be treated as core for SHIP1 
    across hematopoietic cells versus retained as cell-type-specific downstream 
    consequences?
  experts:
  - Hematopoietic signaling experts
  - GO immune process curators
- question: How should Alzheimer/microglial relevance for INPP5D be represented 
    without over-annotating disease progression mechanisms as core molecular 
    function?
  experts:
  - Microglial biology experts
  - Alzheimer disease genetics curators
suggested_experiments:
- description: 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.
  experiment_type: domain-resolved immune signaling rescue assay
- description: 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.
  experiment_type: microglial phosphoinositide signaling perturbation assay

Gene Description

Existing Annotations Review

Core Functions

SHIP1 hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, acting as a receptor-proximal brake on PI3K-dependent signaling in immune and hematopoietic cells.

SHIP1 also hydrolyzes soluble inositol polyphosphates, especially Ins(1,3,4,5)P4, linking its catalytic domain to broader inositol phosphate metabolism in hematopoietic signaling contexts.

The SHIP1 SH2 domain binds phosphorylated inhibitory receptor/adaptor motifs, recruiting the catalytic enzyme to immune receptor signaling complexes where it attenuates BCR, Fc, TIGIT, SLAM-family, CD112R, and related pathways.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

INPP5D curation notes

2026-06-19

2026-06-20 Second-Pass Review Notes

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