INPPL1 encodes SHIP2, a phosphatidylinositol (PtdIns) phosphatase that negatively regulates PI3K signaling by hydrolyzing the 5-phosphate of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2 1. Beyond insulin signaling regulation, SHIP2 governs multiple cellular processes including actin cytoskeleton remodeling, cell adhesion, endocytosis, and immune receptor signaling 1. The enzyme is widely expressed across tissues including brain, thymus, heart, and skeletal muscle 2. Clinically, INPPL1 mutations cause opsismodysplasia, a rare autosomal recessive skeletal dysplasia 3. INPPL1 variants are associated with type 2 diabetes susceptibility in both rat and human populations; a 3' UTR deletion in humans results in SHIP2 overexpression and impaired insulin sensitivity 4. The gene has been identified in genome-wide association studies as a diabetic nephropathy locus 5. In cancer, INPPL1 amplification occurs in esophageal squamous cell carcinoma, where SHIP2 modulates AKT phosphorylation and cell proliferation, suggesting potential as a therapeutic target in combination with PLK1 inhibitors 6. Additionally, INPPL1 mutations are comutated with GNAS variants in mucinous gastrointestinal cancers 7.