AMOT (angiomotin) is a multifunctional scaffolding protein that serves as a critical hub integrating mechanotransduction, cell junction homeostasis, and Hippo signaling. Functionally, AMOT maintains tight junctions through formation of complexes that regulate polarity protein uptake 1, and regulates endothelial cell migration and tube formation by modulating actin cytoskeleton dynamics 2. Mechanistically, AMOT acts as a key mechanical rheostat controlling YAP/TAZ activity: its protein stability is dynamically regulated by microtubule-dependent transport to the pericentrosomal proteasome in response to mechanical stimuli, with LATS kinases providing additional protection via phosphorylation 3. AMOT cleavage generates a C-terminal fragment that promotes focal adhesion maturation and leader cell formation during collective migration 4. Disease relevance includes colorectal cancer, where the AMOT-YAP/TAZ axis regulates tumor-associated neutrophil polarization downstream of β-hydroxybutyrate signaling 5, and ulcerative colitis, where the mTOR/PBLD/AMOT pathway controls intestinal barrier repair 6. In osteosarcoma and other malignancies, AMOT generally promotes tumorigenesis through enhanced proliferation and invasion 7, though context-dependent tumor-suppressive roles exist in glioblastoma and lung cancer 8. Clinically, AMOT represents a therapeutic target for cancer and inflammatory bowel disease through modulation of Hippo signaling and mechanotransduction pathways.