RIN2 (Ras and Rab interactor 2) is a guanine nucleotide exchange factor (GEF) that activates the small GTPase Rab5 to regulate endocytic trafficking 1. In endothelial cells, the RIN2/Rab5C complex prevents lysosomal degradation of internalized VEGFR2, maintaining receptor signaling through ERK and PI3K pathways essential for angiogenic tip cell specification and sprouting 2. RIN2 also functions as an effector of R-Ras, promoting selective endocytosis of active β1 integrins and activating Rac1-dependent cell adhesion via TIAM1 signaling 1. Additionally, insulin stimulation induces pro-reductive shifts in RIN2 cysteine modifications that modulate insulin signal transduction in skeletal muscle 3. Biallelic RIN2 mutations cause RIN2 syndrome (formerly MACS syndrome), an autosomal recessive connective tissue disorder characterized by progressive facial coarsening, sparse hair, skin laxity, scoliosis, joint hypermobility, and dental abnormalities 45. The disorder results from impaired intracellular trafficking due to RIN2 deficiency, with ultrastructural collagen fibril abnormalities and organellar dysfunction in fibroblasts 6. Expanding clinical features include leukoencephalopathy, bronchiectasis, hypergonadotropic hypogonadism, and cervical vertebral fusion 75.