IPCEF1 (interaction protein for cytohesin exchange factors 1) is a scaffold protein that enhances guanine-nucleotide exchange factor activity on the small GTPase ARF6. Mechanistically, IPCEF1 binds to cytohesin 2 through its C-terminal 121 amino acids and the cytohesin coiled-coil domain, increasing ARF6-GTP formation both in vitro and in vivo 1. IPCEF1 co-localizes with cytohesin 2 in the cytosol and translocates to the plasma membrane upon cell stimulation, where it facilitates HGF-dependent ARF6 activation and epithelial cell migration 2. Notably, IPCEF1 represents the C-terminal half of the CNK3 scaffold protein 2. Clinically, IPCEF1 dysregulation associates with multiple malignancies. IPCEF1 is downregulated in papillary thyroid carcinoma (PTC) with lymph node metastasis 3 and exhibits altered circular RNA expression (hsa_circ_IPCEF1) that correlates with PTC pathogenesis through miRNA sponging 4. IPCEF1 appears in prognostic models for radioactive iodine response in PTC 5 and sarcoma prognosis 6. Additionally, IPCEF1 variants associate with chr6 lymphocytic leukemia susceptibility 7, while upregulation occurs in idiopathic pulmonary arterial hypertension, potentially contributing to aberrant oxygen transport and smooth muscle migration 8.