DENND1C (Connecdenn 3) is a guanine nucleotide exchange factor (GEF) that activates the small GTPase Rab35 by catalyzing GDP-to-GTP exchange 1. Unlike related DENN domain proteins, DENND1C contains a unique C-terminal actin-binding motif that directly couples Rab35 activation to actin cytoskeleton dynamics, promoting membrane protrusions and cell shape alterations 2. This interaction facilitates Rab35-dependent recruitment of actin-bundling proteins like fascin, distinguishing DENND1C's role in cytoskeletal regulation from other Rab35-GEFs that primarily govern endosomal trafficking 2. Disease relevance of DENND1C is emerging across multiple conditions. In psychiatric disorders—schizophrenia, bipolar disorder, and major depressive disorder—DENND1C forms immune complexes in patient serum and shows strong correlation with symptom severity; notably, DENND1C is absent in healthy controls and decreases following electroconvulsive therapy 3. In melanoma, DENND1C appears within a PCSK9-regulated gene network that predicts resistance to immune checkpoint blockade therapy 4. Additionally, differential DNA methylation of DENND1C associates with obesity-related metabolic dysfunction and correlates with fasting glucose levels in adipose tissue 5. These findings suggest DENND1C may serve as a biomarker for psychiatric treatment response and immune evasion in cancer, though its precise mechanistic contributions to these pathologies require further investigation.