LSM12 (Like-Sm protein 12) is a multifunctional RNA-binding protein with dual roles in calcium signaling and RNA splicing. Primary function: LSM12 acts as a NAADP-binding protein that confers NAADP sensitivity to two-pore channel (TPC) complexes, enabling NAADP-evoked Ca2+ release from endosomes and lysosomes 1. Unlike direct TPC binding, LSM12 functions as an accessory protein that works convergently with JPT2 to regulate endolysosomal calcium signaling and intracellular trafficking 2. Mechanism: LSM12 binds NAADP with high affinity and independently associates with TPC1 and TPC2 to support calcium-dependent cellular processes 1. Additionally, LSM12 regulates alternative splicing of target genes including USO1 and ARRB1, promoting exon inclusion or skipping patterns that affect protein isoform expression 3, 4. Disease relevance: LSM12 is significantly upregulated in multiple cancers—oral squamous cell carcinoma, lung squamous cell carcinoma, and colorectal cancer—where it promotes proliferation, migration, invasion, and inhibits apoptosis 3, 4, 5. In colorectal cancer, LSM12 activates WNT/CTNNB1 signaling by directly binding β-catenin and stabilizing its protein levels 5. LSM12 also sustains neuroprotection in C9-ALS/FTD by maintaining the nucleocytoplasmic RAN gradient through EPAC1 upregulation 6. Clinical significance: LSM12 is a potent diagnostic and prognostic biomarker for cancer, with potential as a therapeutic target in multiple malignancies 3.