The Duality of Cdk5: A Master Regulator in Neurodevelopment and a Hijacked Oncogene in Cancer.

Cyclin-dependent kinase 5 (Cdk5) is an atypical serine/threonine kinase distinct from classical cell cycle regulators. Its activity is highest in the nervous system and essential for development, but its functions in other tissues, particularly in cancer, are increasingly being elucidated. This review explores the functional duality of Cdk5 by comparing its constructive role in neurodevelopment with its repurposed oncogenic function in cancer. In neurodevelopment, Cdk5 orchestrates nearly every stage of brain construction, including neuronal differentiation, migration, and synaptic plasticity. However, in many cancers, this neurodevelopmental toolkit is repurposed, and aberrantly activated Cdk5 promotes proliferation, metastasis, and therapeutic resistance in diverse solid tumors. Cdk5 also actively shapes the tumor microenvironment by promoting angiogenesis and modulating immunity. Notably, this oncogenic function is not universal, as Cdk5 exhibits its duality even within the context of cancer; it acts as a tumor suppressor in gastric cancer upon nuclear localization. Taken together, these lines of evidence underscore that Cdk5 is a context-dependent kinase whose output is determined by upstream regulation, subcellular localization, and the cellular environment. This review discusses the molecular basis of its dual role and highlights both the potential and complexity of Cdk5 as a therapeutic target in oncology.