DENND2B is a DENN domain-containing guanine nucleotide exchange factor (GEF) localized to chromosome 11 that regulates multiple aspects of cell division and trafficking. Its primary function involves activating small GTPases: it functions as a Rab35 GEF at the intercellular bridge during cytokinesis 1 and as a Rab13 GEF at the leading edge of migrating cells 2. During cytokinesis, DENND2B recruits and activates Rab35 to promote actin depolymerization and ESCRT-III recruitment, enabling proper abscission; DENND2B knockdown causes multinucleated cells and activates the abscission checkpoint 1. In cancer cells, DENND2B-mediated Rab13 activation at cell peripheries promotes invasive behavior and metastasis through interaction with effector MICAL-L2 2. DENND2B also regulates EGFR recycling through interaction with intersectin-s, a mechanism disrupted by PKD-mediated phosphorylation upon EGF stimulation 3. Clinically, monoallelic loss-of-function DENND2B variants cause autosomal dominant neurodevelopmental disorder featuring developmental delay, intellectual disability, epilepsy, and vulnerability to psychosis or catatonia 4. Rare variants associate with carotid plaque susceptibility through SCUBE2 eQTL effects 5. These findings establish DENND2B as a critical regulator of cell division, trafficking, and development with implications for cancer progression and neuropsychiatric disease.