SMAP1 (small ArfGAP 1) is a GTPase-activating protein located on chromosome 6 that specifically regulates ARF6, a small GTPase controlling membrane trafficking and actin remodeling 1. The protein functions primarily in clathrin-dependent endocytosis, where it promotes transferrin receptor internalization and can functionally overlap with SMAP2 in this process 2. SMAP1 plays a critical role in the hematopoietic microenvironment by being induced in stromal cells upon contact with erythroid cells, suggesting involvement in erythropoiesis and hematopoietic progenitor-stromal cell interactions 3. Beyond endocytosis, SMAP1 regulates Weibel-Palade body biogenesis in endothelial cells by preventing degradation and maintaining appropriate secretory granule size 4. Clinically, SMAP1 mutations are frequently disrupted in microsatellite-unstable colorectal cancers, with loss-of-function mutations increasing cell proliferation and clonogenicity while paradoxically reducing invasiveness 1. SMAP1 functions redundantly with Pals1 to inhibit Arf6/Rac1-dependent colorectal cancer cell migration; simultaneous downregulation of both genes significantly reduces patient survival 5. Smap1-deficient mice develop myelodysplastic syndrome and acute myeloid leukemia, indicating that deregulated clathrin-dependent trafficking contributes to hematological malignancies 6. Additionally, rare SMAP1 variants associate with pediatric venous thromboembolism 7, though SMAP1's role in depression treatment outcomes requires further investigation 8.