AMOTL1 (angiomotin-like 1) is a multifunctional actin-binding scaffolding protein that regulates cell polarity, adhesion, and migration 1. As a member of the Motin family, AMOTL1 integrates into the Hippo signaling pathway with context-dependent functions 2. While the UniProt annotation suggests AMOTL1 inhibits Wnt/β-catenin signaling, recent evidence reveals more complex roles in Hippo pathway regulation. In several cancers, AMOTL1 promotes YAP1 nuclear accumulation and stability through direct protein-protein interaction, protecting YAP1 from ubiquitin-mediated degradation and enabling oncogenic transcription of targets like CTGF and c-Myc 3. This pro-tumorigenic function has been demonstrated in gastric cancer, breast cancer, glioma, nasopharyngeal carcinoma, and prostate cancer 4567. The tumor suppressor Merlin antagonizes AMOTL1 through proteasomal degradation, while YAP stimulates AMOTL1 expression, creating a regulatory feedback loop 4. Clinically, elevated AMOTL1 expression correlates with poor prognosis and reduced survival rates across multiple cancer types. In genetic disease, heterozygous AMOTL1 variants—particularly affecting amino acids 157-161—define a new orofacial clefting syndrome with congenital heart disease and tall stature 1. AMOTL1 function appears highly context-dependent, with oncogenic properties in somatic cancers but essential roles in normal development 8.