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

Src homology 2 domain-containing inositol phosphatase 1 (SHIP1) is a 145 kDa phosphatase primarily expressed in hematopoietic cells and is a key negative regulator of the PI3K/Akt signaling pathway [1, 2]. It functions by dephosphorylating the secondary messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) to phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), thereby preventing the membrane recruitment and activation of pro-survival kinases like Akt [1, 3]. This enzymatic activity is crucial for maintaining immune homeostasis and preventing excessive inflammatory responses [3]. In clinical contexts, SHIP1 is often downregulated or mutated in hematological malignancies like acute myeloid leukemia, leading to uncontrolled cell growth [2]. Furthermore, SHIP1 has been identified as a genetic risk factor for Alzheimer's disease, where it modulates microglial activation and amyloid-beta clearance [4]. Drug development efforts have focused on allosteric activators, such as AQX-1125, to treat inflammatory conditions like interstitial cystitis and COPD by reducing cytokine production [5]. Additionally, SHIP1 inhibitors are being investigated for their potential to enhance the efficacy of cancer immunotherapies by boosting the activity of natural killer cells and macrophages [3].

Other names

INPP5DSHIP-1p150ShipInositol polyphosphate-5-phosphatase of 150 kDaPhosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1SIP-110hp150SHIP

Small molecule 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.