Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 (INPP5D)
The protein contains 1189 amino acids for an estimated molecular weight of 133292 Da.
Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways (PubMed:8723348, PubMed:10764818, PubMed:8769125). Able also to hydrolyzes the 5-phosphate of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (PubMed:9108392, PubMed:10764818, PubMed:8769125). Acts as a negative regulator of B-cell antigen receptor signaling. Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. Regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity (PubMed:16682172). Key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates the activin/TGF-beta-induced apoptosis through its Smad-depen (updated: July 3, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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| Variant | Description |
|---|---|
| one patient with acute myeloid leukemya; somatic mutation | |
| dbSNP:rs9247 |
Biological Process
Apoptotic process
Blood coagulation
Cytokine-mediated signaling pathway
Determination of adult lifespan
Immunoglobulin mediated immune response
Inositol phosphate metabolic process
Intracellular signal transduction
Leukocyte migration
Negative regulation of B cell proliferation
Negative regulation of bone resorption
Negative regulation of immune response
Negative regulation of interleukin-6 biosynthetic process
Negative regulation of interleukin-6 production
Negative regulation of monocyte differentiation
Negative regulation of neutrophil differentiation
Negative regulation of osteoclast differentiation
Negative regulation of signal transduction
Phosphate-containing compound metabolic process
Phosphatidylinositol biosynthetic process
Phosphatidylinositol dephosphorylation
Phospholipid metabolic process
Positive regulation of apoptotic process
Positive regulation of B cell differentiation
Positive regulation of erythrocyte differentiation
Signal transduction
Small molecule metabolic process
T cell receptor signaling pathway
Molecular Function
Inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity
Inositol-1,4,5-trisphosphate 5-phosphatase activity
Inositol-polyphosphate 5-phosphatase activity
Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity
Phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
PTB domain binding
SH3 domain binding
The reference OMIM entry for this protein is 601582
Inositol polyphosphate-5-phosphatase, 145-kd; inpp5d
Sh2-containing inositol phosphatase; ship
Ship1
CLONING
The phosphatidylinositols serve as precursors for a number of different messenger molecules. Agonist stimulation of cells results in phosphatidylinositol turnover and the generation of inositol 1,4,5-triphosphate (Ins(1,4,5)P3), which mobilizes intracellular calcium. The inositol-polyphosphate 5-phosphatase (INPP5) enzymes hydrolyze Ins(1,4,5)P3 in a signal-terminating reaction. Known INPP5s include the 40-kD INPP5A (600106), the 75-kD INPP5B (147264), and the enzyme associated with Lowe oculocerebrorenal syndrome (300535). Damen et al. (1996) cloned and sequenced a cDNA encoding a 145-kD protein from a mouse hematopoietic cell line; the protein became tyrosine phosphorylated and associated with SHC (600560) after cytokine stimulation. Based on its domains and enzymatic activity, Damen et al. (1996) named this protein SHIP for 'SH2-containing inositol phosphatase.' Ware et al. (1996) described the cloning of the human homolog of murine Ship from a human megakaryocytic cell line cDNA library using 2 nonoverlapping mouse Ship cDNA fragments as probes. Northern blot analysis suggested that human SHIP is expressed as a 5.3-kb mRNA in bone marrow and a wide variety of other tissues. Sequence analysis of the cDNA predicted a protein of 1,188 amino acids exhibiting 87.2% overall sequence identity with mouse Ship. Contained within the defined open reading frame was an N-terminal, group I src homology (SH2) domain; 3 NXXY motifs that, if phosphorylated, could be bound by phosphotyrosine-binding (PTB) domains; a C-terminal proline-rich region; and 2 centrally located inositol polyphosphate 5-phosphatase motifs. Using the sequences of known inositol and phosphatidylinositol polyphosphate 5-phosphatases, Drayer et al. (1996) designed degenerate oligonucleotides and subsequently cloned a novel 5-phosphatase, which they called 51CN. They cloned a full-length cDNA from a human placenta library and found that it encodes a 1,188-amino acid protein with a predicted molecular mass of 133 kD. The sequence predicted an N-terminal region containing an SH2 domain, a central 5-phosphatase domain, and a C-terminal proline-rich region with consensus sites for SH3-domain interactions. Northern blot analysis revealed a 5-kb message expressed strongly in placenta and heart and weakly in brain and lung tissues. The authors also noted the presence of an 8-kb transcript in heart and skeletal muscle. Following expression in COS-7 cells, Drayer et al. (1996) showed that this enzyme has a specificity for substrates phosphorylated at the 3-position. Kavanaugh et al. (1996) found 3 splice variants of the 51CN gene which, based on their molecular masses, they termed SIP-110, SIP-130, and SIP-145. The SIP-110 protein was isolated based on its binding to the SH3 domain of GRB2 (108355). The SIP-130 and SIP-145 proteins were isolated based on their binding to the PTB domain of SHC. The authors stated that INPP5s may be associated with GRB2- and SHC-mediated signal transduction. By using a modified yeast 2-hybrid system to find proteins that bind the SHC phosphotyrosine-binding domain, Lioubin et al. (1996) independently cloned INPP5D and designated it p150(Ship).GENE FUNCTION
Liu et al. (1998) studied the expression of the Ship gene during mouse development. They found that the gene is expressed in late primitive-streak stage embryos (7.5 days postcoitum), when hematopoiesis is thought to begin, and the expression is restricted to the hematopoiet ... More on the omim web site
July 4, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 12, 2019: Protein entry updated
Automatic update: model status changed
Nov. 17, 2018: Protein entry updated
Automatic update: model status changed
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
Oct. 27, 2017: Protein entry updated
Automatic update: model status changed
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601582 was added.
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed