MAST1 is a microtubule-associated serine/threonine kinase essential for correct brain development 1. It functions as a post-mitotic neuronal protein present in dendritic and axonal compartments 1, regulating neuronal differentiation through P27-mediated cell cycle arrest 2. In cancer cells, MAST1 drives cisplatin resistance by rewiring MEK activation in a cRaf-independent manner 3. MAST1 protein stability is regulated through deubiquitination: USP1 and USP28 both interact with MAST1, preventing K48-linked polyubiquitination and extending its half-life 45. Additionally, heat shock protein 90B (hsp90B) protects MAST1 from proteasomal degradation by blocking ubiquitination at lysines 317 and 545 6. Disease relevance: De novo MAST1 mutations cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations 1, exhibiting a dominant-negative mode of action 1. Rare variants in MAST1 also associate with familial breast cancer susceptibility 7 and early-onset cerebellar atrophy with ataxia 8. Combined pharmacological inhibition of USP1/USP28 with MAST1 inhibitors synergistically enhances cisplatin efficacy, suggesting a therapeutic strategy for cisplatin-resistant cancers 45.