RAB40B is an atypical Rab GTPase that functions as a substrate-recognition component of the ECS(RAB40B) E3 ubiquitin ligase complex, regulating cell migration and invasion through targeted protein ubiquitination 12. Unlike typical Rab proteins, RAB40B contains a unique SOCS box domain that enables assembly of the CRL5 E3 ligase complex 31. The protein operates through two primary mechanisms: as part of the ECS complex, GTP-bound RAB40B promotes ubiquitination and degradation of LIMA1/EPLIN, regulating leading-edge actin dynamics, and ubiquitinates RAP2A GTPase to control its localization and activation in lamellipodia 12. Additionally, RAB40B functions independently by binding TKS5 effector protein to mediate trafficking of MMP2 and MMP9 to invadopodia, promoting extracellular matrix degradation during cancer invasion 45. Clinical significance includes associations with cancer progression, as elevated RAB40B expression correlates with gastric cancer invasion, lymph node metastasis, and poor survival 6. Mutations affecting the SOCS box cause axonal peripheral neuropathy (Charcot-Marie-Tooth disease type 2), demonstrating its critical role in neuronal function 3. RAB40B represents a therapeutic target, as its activity is regulated by tumor suppressor miRNA miR-204 4.