PHACTR4 (phosphatase and actin regulator 4) is a tumor suppressor protein that regulates cellular proliferation, migration, and cytoskeletal dynamics through protein phosphatase 1 (PP1) activation and actin binding 1. The protein acts as a PP1 activator by preventing phosphorylation of PPP1CA, leading to downstream effects on cell cycle regulation and cytoskeletal remodeling 2. PHACTR4 localizes to membrane protrusions where it interacts with active Arp2/3 complex and regulates ezrin phosphorylation, coordinating membrane retraction during macrophage migration and phagocytosis 2. Loss of PHACTR4 function disrupts lamellipodial architecture and impairs coordinated cell migration 2. The gene functions as a tumor suppressor, with depletion leading to increased proliferation, transformation, and soft agar colony formation through an Rb-dependent pathway 1. PHACTR4 is significantly deleted or mutated across multiple cancer types and shows reduced expression in hepatocellular carcinoma, where it inhibits the IL-6/Stat3 pathway 3. Additionally, PHACTR4 downregulation is associated with diabetic nephropathy, correlating with glomerular endothelial dysfunction and inflammatory infiltration 4. De novo missense variants in PHACTR4's RPEL3 domain are linked to congenital anomalies including cleft palate and neurodevelopmental abnormalities 5.