TAOK2 (TAO kinase 2) is a serine/threonine-protein kinase functioning as a key regulator of neuronal development, stress responses, and cellular morphogenesis. Primary Function: TAOK2 orchestrates multiple signaling cascades through phosphorylation of MAP2K3/MAP2K6 kinases, activating the p38 MAPK pathway in response to DNA damage and stress 1. The protein exists as two functionally distinct isoforms: isoform 1 regulates apoptotic morphological changes including membrane blebbing and cell contraction through MAPK8/JNK activation, while isoform 2 mediates protocadherin-8 endocytosis via p38 MAPK signaling [UniProt]. Mechanism: TAOK2 regulates primary cilia length through kinase activity independent of its catalytic function on tubulins, with TAOK2 loss resulting in elongated cilia and impaired sonic hedgehog signaling 2. In neurons, TAOK2 promotes dendrite and synapse development through RhoA signaling activation, with reduced TAOK2 activity causing diminished excitatory neurotransmission and defective neural connectivity 3. Disease Relevance: TAOK2 variants cause a distinct neurodevelopmental disorder (TAOK2-NDD) characterized by neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and early-onset obesity (70%) 4. The 16p11.2 deletion involving TAOK2 produces sex-specific striatal behavioral deficits through translation dysregulation and ERK signaling alterations 5. Clinical Significance: TAOK2 represents a potential therapeutic target in cancer development through regulation of cell proliferation and apoptosis 1, with evidence suggesting oncogenic roles in prostate cancer progression 6.