AMOTL2 is a scaffold protein that regulates endothelial cell morphology and vascular homeostasis through multiple interconnected pathways. Functionally, AMOTL2 anchors radial actin fibers to CDH1 junction complexes, facilitating actin cytoskeleton organization and mechanical force transmission across the endothelial cell 1. It connects VE-cadherin and actin filaments to the nuclear lamina, enabling mechanotransduction of blood flow-derived forces 2. Mechanistically, AMOTL2 activates Hippo signaling by recruiting LATS2 kinase, which phosphorylates YAP1 and excludes it from the nucleus, thereby repressing YAP1-driven transcription 345. AMOTL2 also inhibits Wnt/β-catenin signaling by trapping β-catenin in recycling endosomes 6. Additionally, AMOTL2 promotes MAPK/ERK activation via c-Src-dependent mechanisms, supporting endothelial cell migration and proliferation during angiogenesis 7. Disease relevance: AMOTL2 dysregulation contributes to vascular pathology. Endothelial AMOTL2 deficiency provokes pro-inflammatory responses and abdominal aortic aneurysm formation 2. A CAD GWAS variant linked to AMOTL2 was functionally validated, suggesting involvement in coronary artery disease 8. AMOTL2 is downregulated in nasopharyngeal carcinoma through ARNTL2-mediated transcriptional suppression, promoting metastasis via enhanced YAP signaling 9. Clinically, AMOTL2 represents a potential therapeutic target for vascular diseases and metastatic cancers.