ANKLE2 is a scaffolding protein with dual roles in cell division and neural development. During mitosis, ANKLE2 coordinates nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 through inhibition of VRK1 kinase and recruitment of protein phosphatase 2A (PP2A) 1. Structural and functional evidence suggests ANKLE2 functions as a regulatory subunit of PP2A and localizes to the reassembling nuclear envelope via interaction with ER protein Vap33 2. In neural progenitor cells, ANKLE2 is essential for asymmetric cell division by regulating Par complex function and ER/nuclear envelope morphology; loss of ANKLE2 disrupts spindle alignment and reduces progenitor cell numbers 3. Pathogenic loss-of-function mutations in ANKLE2 cause primary congenital microcephaly (MCPH16), characterized by reduced brain volume, simplified cortical gyration, callosal abnormalities, and developmental delays 4. Additionally, Zika virus NS4A protein specifically targets ANKLE2, hijacking it to promote viral replication while simultaneously causing microcephaly through disruption of developing neural tissues 56. ANKLE2 dysfunction is also linked to tauopathy and cancer, highlighting its broader disease relevance beyond microcephaly.