ITPRID2 (also known as KRAP, KRas-induced actin-interacting protein) is a cytoplasmic protein that functions as a critical regulator of inositol 1,4,5-trisphosphate receptor (IP3R) activity and calcium signaling. Primary Function: ITPRID2 tethers IP3R clusters to filamentous actin beneath the plasma membrane, serving as a licensing factor that determines which IP3Rs respond to stimulation 1. The protein is ubiquitously expressed across tissues with high levels in pancreas, liver, and brown adipose tissues, where it colocalizes with actin along apical membranes 2. Mechanism: ITPRID2 regulates calcium transfer from the endoplasmic reticulum to mitochondria by both licensing IP3R activity and stabilizing ER-mitochondrial membrane contact sites (ERMCSs) 3. Loss of ITPRID2 abolishes cytosolic and mitochondrial calcium signals, while overexpression enhances calcium puffs and global calcium signaling 1. Disease Relevance: ITPRID2 is implicated in cancer pathogenesis, being upregulated in colorectal cancer and identified as a macrophage-associated prognostic gene in bladder cancer 42. Additionally, ITPRID2-deficient mice demonstrate altered energy metabolism and resistance to diet-induced obesity and diabetes 5. Clinical Significance: As a component of prognostic models in cancer and a potential metabolic disease target, ITPRID2 represents a multifunctional protein linking cytoskeletal organization, calcium signaling, and disease pathogenesis.