FAT atypical cadherin 1 (FAT1) (FAT1)

FAT atypical cadherin 1 (FAT1) is a large transmembrane protein belonging to the cadherin superfamily that plays a pivotal role in regulating cell-cell adhesion and intracellular signaling. It acts as a scaffold for various signaling molecules, most notably modulating the Hippo-YAP and Wnt/beta-catenin pathways to control cell proliferation, migration, and polarity [1, 2]. In human pathology, FAT1 is frequently identified as a tumor suppressor, with loss-of-function mutations occurring at high frequencies in squamous cell carcinomas of the head and neck, lung, and esophagus [3, 4]. However, its role is context-dependent, as it can also function as an oncogene in certain leukemias and solid tumors by promoting invasive phenotypes [5]. Beyond oncology, FAT1 is critical for the development and maintenance of the kidney's glomerular filtration barrier and the musculoskeletal system, with mutations linked to nephrotic syndrome and facioscapulohumeral muscular dystrophy [6]. While no drugs targeting FAT1 mRNA or protein are currently FDA-approved, FAT1 status is a significant biomarker for predicting resistance to CDK4/6 inhibitors like abemaciclib [7]. Experimental therapeutic approaches, including the use of siRNA to target FAT1 mRNA and monoclonal antibodies to inhibit the protein, are currently under investigation in preclinical research [8].

Other names

FATCDHF7CDHR8hFat1Fat atypical cadherin 1FAT1

Experimental strategies primarily utilize RNA interference (siRNA) or antisense oligonucleotides to knockdown FAT1 mRNA levels, or monoclonal antibodies to block extracellular domain interactions. Additionally, FAT1 loss serves as a mechanism of resistance to CDK4/6 inhibitors by activating the Hippo-YAP signaling pathway.