INPP5D | Inositol polyphosphate phosphatases | IUPHAR/BPS Guide to PHARMACOLOGY

INPP5D

Target id: 1455

Nomenclature: INPP5D

Abbreviated Name: SHIP1

Family: Inositol polyphosphate phosphatases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     INPP5D has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1189 2q37.1 INPP5D inositol polyphosphate-5-phosphatase D
Mouse - 1191 1 C5 Inpp5d inositol polyphosphate-5-phosphatase D
Rat - 1191 9q35 Inpp5d inositol polyphosphate-5-phosphatase D
Gene and Protein Information Comments
Alternative transcripts and protein isoforms for the human and mouse genes have been identified. We provide details and links for the longest transcripts and isoforms. Further information is available from the Entrez gene links below.
Previous and Unofficial Names
Inositol polyphosphate-5-phosphatase 145 kDa | inositol polyphosphate-5-phosphatase D | phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 | SH2 domain-containing inositol 5'-phosphatase 1 | Src homology 2 domain-containing inositol-5-phosphatase | inositol polyphosphate-5-phosphatase, 145kDa
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.1.3.86
Description Reaction Reference
Hydrolysis of the 5' phosphate of phosphatidylinositol (PtdIns) trisphosphate to PtdIns 3,4 biphosphate 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate + H(2)O <=>> 1-phosphatidyl-1D-myo-inositol 3,4-diphosphate + phosphate

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
rosiptor Hs Activation - - 5
[5]
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
3 alpha-aminocholestane Hs Inhibition - - 1
[1]
Immunopharmacology Comments
SHIP1 activators are proposed as novel anti-inflammatory agents e.g. rosiptor (AQX-1125) which is in Phase 2 and 3 clinical trials [3,5]. In contrast, SHIP1 inhibitors may have clinical utility in allogeneic transplantation via upregulation of immune regulatory cell numbers [1].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0050900 leukocyte migration TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 8 GO processes
GO:0050852 T cell receptor signaling pathway TAS
click arrow to show/hide IEA associations
GO:0030889 negative regulation of B cell proliferation IEA
GO:0045579 positive regulation of B cell differentiation IEA
GO:0045648 positive regulation of erythrocyte differentiation IEA
GO:0045656 negative regulation of monocyte differentiation IEA
GO:0045659 negative regulation of neutrophil differentiation IEA
GO:0045671 negative regulation of osteoclast differentiation IEA
GO:0050777 negative regulation of immune response IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0050900 leukocyte migration TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 3 GO processes
GO:0050852 T cell receptor signaling pathway TAS
click arrow to show/hide IEA associations
GO:0030889 negative regulation of B cell proliferation IEA
GO:0045579 positive regulation of B cell differentiation IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0016064 immunoglobulin mediated immune response IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 3 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0016064 immunoglobulin mediated immune response IEA
GO:0030889 negative regulation of B cell proliferation IEA
GO:0045579 positive regulation of B cell differentiation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 5 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0045579 positive regulation of B cell differentiation IEA
GO:0045648 positive regulation of erythrocyte differentiation IEA
GO:0045656 negative regulation of monocyte differentiation IEA
GO:0045659 negative regulation of neutrophil differentiation IEA
GO:0045671 negative regulation of osteoclast differentiation IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0045409 negative regulation of interleukin-6 biosynthetic process IEA
Immuno Disease Associations
Disease Name:  Interstitial cystitis
Disease Synonyms:  no synonynms
Comment:  Phase 3 evaluating the SHIP1 activator rosiptor is underway (see NCT02858453).
Disease X-refs:  Disease Ontology: DOID:13949
References: 
Disease Name:  Atopic dermatitis
Disease Synonyms:  no synonynms
Comment:  Target of activating compounds with potential immunosuppressant action. Phase 2 with rosiptor has been completed for atopic dermatitis.
Disease X-refs:  Disease Ontology: DOID:3310
OMIM: 603165
References: 
Physiological Consequences of Altering Gene Expression
SHIP-deficient mice accept allogeneic bone marrow transplants without significant graft-vs-host disease. They produce elevated levels of myeloid suppressor cells which impairs priming of allogeneic T cells, hence the improved tolerance seen in transplant experiments.
Species:  Mouse
Tissue: 
Technique: 
References:  2,4
General Comments
Expression of this protein is restricted to hematopoietic cells. It functions as a negative regulator of myeloid cell proliferation and survival. The phosphatase activity of SHIP1 negatively regulates phosphoinositide 3-kinase (PI3K) signalling pathways.

References

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1. Brooks R, Fuhler GM, Iyer S, Smith MJ, Park MY, Paraiso KH, Engelman RW, Kerr WG. (2010) SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells. J. Immunol., 184 (7): 3582-9. [PMID:20200281]

2. Ghansah T, Paraiso KH, Highfill S, Desponts C, May S, McIntosh JK, Wang JW, Ninos J, Brayer J, Cheng F et al.. (2004) Expansion of myeloid suppressor cells in SHIP-deficient mice represses allogeneic T cell responses. J. Immunol., 173 (12): 7324-30. [PMID:15585856]

3. Nickel JC, Egerdie B, Davis E, Evans R, Mackenzie L, Shrewsbury SB. (2016) A Phase II Study of the Efficacy and Safety of the Novel Oral SHIP1 Activator AQX-1125 in Subjects with Moderate to Severe Interstitial Cystitis/Bladder Pain Syndrome. J. Urol., 196 (3): 747-54. [PMID:26968644]

4. Paraiso KH, Ghansah T, Costello A, Engelman RW, Kerr WG. (2007) Induced SHIP deficiency expands myeloid regulatory cells and abrogates graft-versus-host disease. J. Immunol., 178 (5): 2893-900. [PMID:17312133]

5. Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, Toews J, Wu J, Ogden N, MacRury T et al.. (2013) Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br. J. Pharmacol., 168 (6): 1506-18. [PMID:23121445]

How to cite this page

Inositol polyphosphate phosphatases: INPP5D. Last modified on 12/05/2017. Accessed on 21/09/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1455.