HOOK3 (hook microtubule tethering protein 3) serves as a critical scaffold protein that coordinates bidirectional cargo transport by linking opposite-polarity microtubule motors dynein and kinesin-3 KIF1C 1. The protein functions as a cargo adaptor that binds to and activates cytoplasmic dynein-1/dynactin complex while simultaneously interacting with KIF1C through its tail region, enabling dynein to transport KIF1C toward microtubule minus ends and KIF1C to transport dynein toward plus ends 1. HOOK3 forms part of the FHF complex with FTS and FHIP proteins, which exists in an autoinhibited state that KIF1C can relieve to activate cargo transport 2. The protein also activates KIF1C by relieving its autoinhibitory interactions, working alongside PTPN21 to enable cargo-activated transport 3. HOOK3 demonstrates significant disease relevance, with reduced expression observed in Alzheimer's disease leading to slowed endosomal transport and increased β-amyloid production 4. In cancer, HOOK3 exhibits tumor-suppressive properties in gastric cancer by regulating the SP1/VEGFA pathway 5, while amplification in bladder urothelial carcinoma correlates with improved patient survival 6. These findings highlight HOOK3's dual role in maintaining cellular transport homeostasis and its potential therapeutic significance in neurodegenerative diseases and cancer.