SHROOM2 is an actin-binding protein that regulates cytoskeletal organization and epithelial cell architecture through multiple mechanisms. Structurally, SHROOM2 contains a PDZ domain and directly interacts with F-actin, myosin VIIa, and the tight junction protein ZO-1, forming a junctional scaffolding complex that bridges the membrane to underlying cytoskeleton 1. In retinal pigment epithelium, SHROOM2 regulates melanosome biogenesis and apical localization through gamma-tubulin redistribution and Rab27a-dependent mechanisms 2. SHROOM2 mediates the RhoA-ROCK pathway controlling stress fiber formation and focal adhesion, while also suppressing epithelial-to-mesenchymal transition (EMT) and tumor metastasis in nasopharyngeal carcinoma through both ROCK-dependent and -independent mechanisms 3. Disease relevance is substantial: SHROOM2 downregulation correlates with cancer progression, with higher upregulation associated with poor prognosis in breast cancer and linked to immune checkpoint expression and tumor mutational burden 4. Rare damaging variants in SHROOM2 disrupt ROCK1 binding and contribute to neural tube defect risk 5, while common variants near SHROOM2 influence colorectal cancer susceptibility 6. In hepatocellular carcinoma, the lnc-MAP3K13-3:1/miR-6894-3p/SHROOM2 axis regulates proliferation, apoptosis, and migration 7.