Microtubule Destabilizer KIF2A Undergoes Distinct Site-Specific Phosphorylation Cascades that Differentially Affect Neuronal Morphogenesis

Neurons exhibit dynamic structural changes in response to extracellular stimuli. Microtubules (MTs) provide rapid and dramatic cytoskeletal changes within the structural framework. However, the molecular mechanisms and signaling networks underlying MT dynamics remain unknown. Here, we have applied a comprehensive and quantitative phospho-analysis of the MT destabilizer KIF2A to elucidate the regulatory mechanisms of MT dynamics within neurons in response to extracellular signals. Interestingly, we identified two different sets of KIF2A phosphorylation profiles that accelerate (A-type) and brake (B-type) the MT depolymerization activity of KIF2A. Brain-derived neurotrophic factor (BDNF) stimulates PAK1 and CDK5 kinases, which decrease the MT depolymerizing activity of KIF2A through B-type phosphorylation, resulting in enhanced outgrowth of neural processes. In contrast, lysophosphatidic acid (LPA) induces ROCK2 kinase, which suppresses neurite outgrowth from round cells via A-type phosphorylation. We propose that these two mutually exclusive forms of KIF2A phosphorylation differentially regulate neuronal morphogenesis during development. [Display omitted] •KIF2A undergoes two different phosphorylation cascades, A-type and B-type•PAK1 and CDK5 induce B-type KIF2A to impede microtubule depolymerization•ROCK2 induces A-type KIF2A to accelerate microtubule depolymerization•A- and B-types of KIF2A phosphorylation respond to extracellular signals in neurons Ogawa and Hirokawa identify two different sets of phosphorylation profiles of the microtubule destabilizer KIF2A that accelerate (A-type) and brake (B-type) the microtubule depolymerization activity of KIF2A within neurons in response to extracellular signals.