DENN domain-containing protein 5A (DENND5A)

DENN domain-containing protein 5A (DENND5A) is a guanine nucleotide exchange factor (GEF) that primarily activates small Rab GTPases such as Rab6, Rab39A/B, and Rab11, thereby regulating intracellular membrane trafficking, especially between endosomes and the trans-Golgi network[1][2][5][6]. It contains several functional domains: an N-terminal DENN domain (the GEF catalytic unit), two RUN domains associated with protein-protein interactions, and a PLAT domain. DENND5A plays important roles in neuronal development by regulating pathways critical for neuron polarity, neurite outgrowth inhibition, and the proper execution of symmetric cell division in neural progenitors[1][3]. Biallelic loss-of-function mutations in DENND5A cause early infantile epileptic encephalopathy-49 (EIEE49), a severe neurodevelopmental disorder often associated with intellectual disability and brain abnormalities[1][3][5]. Disruption of DENND5A in model organisms results in defective neurogenesis due to misaligned mitotic spindles, abnormal cell polarity, and increased commitment to neuron differentiation at the expense of proliferation, highlighting its importance in cortical development[3]. DENND5A is also implicated as a cancer driver candidate due to its roles in regulation of cell cycle and cell migration[2]. There are no currently known therapies targeting DENND5A, but its functions and pathologies make it a protein of significant biological and potentially therapeutic interest.

Other names

DENND5AKIAA1091RAB6IP1Rab6-interacting protein 1DEE49EIEE49FLJ22354FLJ33829FLJ43455DENN/MADD domain containing 5A

Drugs targeting DENND5A would likely modulate its GEF activity toward specific Rab GTPases, affecting vesicular trafficking (no approved drugs currently known)