Role in Cell Migration
Neural precursors are generated in proliferative zones, before migrating to directed locations where they undergo maturation and become functional neurons. Studies in Drosophilia first suggested Numb played a role in cell migration when mutants displayed defective glial migration along axonal tracts. Since then, a mechanism has been discovered through which Numb binds chemotactic signaling receptors, forming a scaffold for atypical PKC (aPKC) recruitment to the receptor complex. Once activated, aPKC phosphorylates Numb, thus promoting a positive feed-forward response that potentiates Numb-chemotactic receptor binding and subsequent endosomal complex formation. Endocytosis supports the relocalization of the chemotactic receptor to the front of the cell to promote receptor-mediated directional migration in response to receptor activation.
Brain-derived neurotrophic factor is among the chemotactic factors that stimulate Numb-mediated chemotaxis during cell migration. BDNF can function as a chemotactic factor for neural precursors during migration by activating TrkB receptors. Numb binds to TrkB receptors to act as an endocytic regulator of TrkB and promote aPKC activation by acting as a scaffolding protein. Once phosphorylated, aPKC can also phosphorylate Numb to increase its efficacy for binding TrkB, thus promoting the precursor’s chemotactic sensitivity to BDNF.
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