REPS1 is a vesicle-associated adaptor protein that functions as a convergence point for insulin and exercise signaling pathways, regulating glucose homeostasis and exocytic cargo delivery. Mechanistically, REPS1 coordinates cellular signaling through multiple pathways: it is phosphorylated at Ser709 by RSK kinase downstream of insulin and exercise stimulation 1, and this phosphorylation is essential for insulin-stimulated muscle glucose uptake 1. Additionally, REPS1 functions within a Reps1-Ralbp1-RalA module that regulates cargo exocytosis by recognizing RalA-GTP at vesicles, promoting surface protein delivery through interactions with the exocyst complex 2. REPS1 forms complexes with endocytic adaptor proteins including ITSN1 and SGIP1 in clathrin-coated pits, implicating it in clathrin-mediated endocytosis and transferrin receptor recycling 34. Disease relevance: REPS1 mutations are associated with neurodegeneration with brain iron accumulation (NBIA), a rare inherited neurological disorder affecting iron and lipid metabolism 5. Clinically, REPS1 phosphorylation at Ser709 is closely linked to whole-body insulin sensitivity and is impaired in insulin-resistant individuals, positioning REPS1 as a potential therapeutic target for metabolic disorders 1.