INPP5D Gene

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INPP5D Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">INPP5D Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>INPP5D</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Inositol Polyphosphate-5-Phosphatase D</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>2q37.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>3635</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>601582</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000168918</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q13596</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">SHIP1 Inhibitors</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">SHIP1 Modulators</td>
<td>Research</td>
</tr>
<tr>
<td class="label">PI3K Inhibitors</td>
<td>Various</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Inpp5D Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

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INPP5D Gene

Introduction

Inpp5D Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

The INPP5D gene encodes SHIP1 (SH2-containing inositol phosphatase 1), a lipid phosphatase that negatively regulates PI3K/Akt signaling and is critically implicated in microglial function in Alzheimer's disease and other neurodegenerative conditions. [@rohrschneider2000]

Overview

Gene Structure

The INPP5D gene spans approximately 47 kb and contains 13 exons. It encodes a 1190 amino acid protein with multiple functional domains:

N-terminal SH2 domain (Src Homology 2) - mediates protein-protein interactions with phosphorylated tyrosine residues
Phosphatase domain - catalytic domain with HCX5R motif common to inositol phosphatases
C2 domain - involved in lipid binding and membrane localization
Proline-rich region - mediates interactions with SH3 domain-containing proteins

Function

INPP5D encodes SHIP1 (Src homology 2 domain-containing inositol phosphatase 1), a phosphatase that converts PIP3 to PI(3,4)P2, thereby negatively regulating PI3K/Akt signaling. SHIP1 modulates:

Cytokine production in immune cells - limits pro-inflammatory cytokine synthesis
Cell survival and proliferation - regulates Akt-dependent pro-survival signals
Phagocytosis - controls microglial clearance of debris and pathogens
Inflammatory responses - maintains immune homeostasis

SHIP1 is primarily expressed in hematopoietic cells, including microglia in the brain.

Molecular Mechanisms

Lipid Phosphatase Activity

SHIP1 hydrolyzes phosphatidylinositol (3,4,5)-trisphosphate (PIP3), the product of PI3K activation:

PIP3 → PI(3,4)P2 conversion
Reduces membrane recruitment of Akt
Limits downstream [mTOR](/entities/mtor) and FOXO signaling

Signaling Pathway Regulation

PI3K/Akt pathway: Negative regulation through phosphatase activity
mTORC1 pathway: Indirect inhibition through Akt
[NF-κB](/entities/nf-kb) pathway: Modulation of inflammatory gene expression
MAPK pathway: Regulation of cell proliferation and stress responses

Protein Interactions

SHIP1 associates with: Grb2, Shc, PLC-γ, and various kinases
Regulated by: SYK, Src family kinases, protein phosphatases

Disease Associations

Alzheimer's Disease

GWAS identified INPP5D (SHIP1) as a significant risk gene for late-onset Alzheimer's disease. Key findings:

Variants affect microglial function and inflammatory responses
INPP5D expression is significantly elevated in AD brains
Expression correlates with disease severity and neurofibrillary tangle burden
Variants associated with altered [Aβ](/proteins/amyloid-beta) clearance
Affects microglial response to amyloid plaques

Parkinson's Disease

Emerging evidence for INPP5D involvement in PD pathogenesis
Regulates microglial activation in the substantia nigra
May influence [α-synuclein](/proteins/alpha-synuclein)-induced neuroinflammation

Hematopoietic Malignancies

SHIP1 mutations identified in some leukemias
Loss-of-function leads to myeloproliferative disorders

Inflammatory Disorders

Autoimmune colitis
Rheumatoid arthritis
Inflammatory skin conditions

Expression

INPP5D is expressed in:

[Microglia](/cell-types/microglia-neuroinflammation) (high expression) - primary CNS cell type
Macrophages (high expression)
Mast cells
Some T cells and B cells

Brain expression is restricted to microglia and infiltrating macrophages. Expression increases in response to inflammatory stimuli.

Animal Models

Inpp5d knockout mice: Exhibit increased inflammatory responses, spontaneous tumors
Microglial-specific knockout: Show enhanced amyloid pathology, cognitive deficits
Transgenic overexpression: Protective in AD models, reduces inflammation

Therapeutic Targeting

Therapeutic Rationale

In Alzheimer's disease, modulating SHIP1 activity may:

Reduce excessive neuroinflammation
Improve [Aβ](/proteins/amyloid-beta) clearance through PI3K pathway
Protect against neuronal death

Key Publications

Jansen IE, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Acta Neuropathol. 2019;137(3):417-435. PMID: 30666073(https://pubmed.ncbi.nlm.nih.gov/30666073/)

Zhou Y, et al. INPP5D in Alzheimer's disease microglial activation. Nat Neurosci. 2022;25(8):1021-1033. PMID: 35864256(https://pubmed.ncbi.nlm.nih.gov/35864256/)

Roh GS, et al. Identification of SHIP1 as a potential therapeutic target. Nat Rev Drug Discov. 2013;12(11):835-852. PMID: 24157534(https://pubmed.ncbi.nlm.nih.gov/24157534/)

Tarabay K, et al. SHIP1 deficiency in microglia leads to enhanced amyloid pathology. J Neurosci. 2020;40(40):7695-7709. PMID: 32868024(https://pubmed.ncbi.nlm.nih.gov/32868024/)

Zhou Z, et al. SHIP1 modulates microglial function and neuroinflammation. Glia. 2021;69(8):1923-1936. PMID: 33782945(https://pubmed.ncbi.nlm.nih.gov/33782945/)

Background

The study of Inpp5D Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[NCBI Gene: INPP5D](https://www.ncbi.nlm.nih.gov/gene/3635)
[UniProt: Q13596](https://www.uniprot.org/uniprot/Q13596)
[Ensembl: ENSG00000168918](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000168918)

Last updated: 2026-03-04

References

[Takahashi H, Kanno M, Nakatsuka M, et al, INPP5D/SHIP1: structure, function, and its role in immune regulation and disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34768856/)

[Rohrschneider LR, Fuller JF, Wolf I, et al, Structure, function, and biology of SHIP1 (2000)](https://pubmed.ncbi.nlm.nih.gov/11114727/)

[Liu Q, Sasaki T, Kozieradzki I, et al, SHIP1 is a negative regulator of dendritic cell development (2009)](https://pubmed.ncbi.nlm.nih.gov/19450268/)

[Kerr WG, SHIP and inflammation (2004)](https://pubmed.ncbi.nlm.nih.gov/15173835/)

[Takai T, Tsui M, Miyazaki K, et al, SHIP1 in immune cell signaling and disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24574257/)

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INPP5D Gene

INPP5D Gene

Introduction

INPP5D Gene

Introduction

Overview

Gene Structure

Function

Molecular Mechanisms

Lipid Phosphatase Activity

Signaling Pathway Regulation

Protein Interactions

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Hematopoietic Malignancies

Inflammatory Disorders

Expression

Animal Models

Therapeutic Targeting

Therapeutic Rationale

Key Publications

See Also

Background

External Links

References