Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1)

Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1) is a 145 kDa protein primarily expressed in hematopoietic cells and is a critical negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway (UniProt: P78527). It functions by dephosphorylating the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) into phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), thereby dampening downstream Akt activation and calcium mobilization (PMID: 21460834). This enzymatic activity is essential for maintaining immune homeostasis and preventing excessive inflammatory responses. Dysregulation or loss of SHIP1 is associated with various pathologies, including Crohn's disease, rheumatoid arthritis, and hematologic malignancies like acute myeloid leukemia (AML) (PMID: 26163518). Consequently, SHIP1 has emerged as a therapeutic target, with small molecule activators being developed to treat inflammatory conditions by restoring its inhibitory control over immune cell activation (ClinicalTrials.gov: NCT02324972). Additionally, its role in microglial function has linked it to the pathogenesis of Alzheimer's disease, expanding its potential as a target in neurodegeneration.

Other names

INPP5DSHIP-1p150ShipSIP-150Inositol polyphosphate 5-phosphatase D

Allosteric activation of the SHIP1 enzyme to increase dephosphorylation of PI(3,4,5)P3, thereby inhibiting the PI3K/Akt signaling pathway; or inhibition of the enzyme to modulate immune cell activity in specific oncology contexts.