Abstract
Neurite growth is controlled by a complex molecular signaling network that regulates filamentous actin (F-actin) dynamics at the growth cone. The evolutionarily conserved ezrin, radixin, and moesin family of proteins tether F-actin to the cell membrane when phosphorylated at a conserved threonine residue and modulate neurite outgrowth. Here we show that Akt binds to and phosphorylates a threonine 573 residue on radixin. Akt-mediated phosphorylation protects radixin from ubiquitin-dependent proteasomal degradation, thereby enhancing radixin protein stability, which permits proper neurite outgrowth and growth cone formation. Conversely, the inhibition of Akt kinase or disruption of Akt-dependent phosphorylation reduces the binding affinity of radixin to F-actin as well as lowers radixin protein levels, resulting in decreased neurite outgrowth and growth cone formation. Our findings suggest that Akt signaling regulates neurite outgrowth by stabilizing radixin interactions with F-actin, thus facilitating local F-actin dynamics.
Highlights
Ezrin, radixin, and moesin, collectively known as ERM proteins, coordinate membrane–cytoskeletal interactions for various forms of cell motility including neuron morphogenesis
We found that an Akt inhibitor decreased radixin protein levels in PC12 cells as assessed by immunoblotting, while MAPK and protein kinase C inhibitors had little effect (Fig. 1B)
Radixin half-life was stabilized in PC12 cells expressing constitutively active (CA) Akt (Fig. 1G), suggesting that Akt kinase controls radixin protein stability rather than expression
Summary
Radixin, and moesin, collectively known as ERM proteins, coordinate membrane–cytoskeletal interactions for various forms of cell motility including neuron morphogenesis. The activity of each ERM protein is regulated by the phosphorylation of a conserved threonine residue in the actin-binding domain (T567 in ezrin, T564 in radixin, and T558 in moesin) that blocks the intramolecular association of the N- and C-terminal regions and allows ERM proteins to bind to F-actin and other proteins[4,5,6,7]. It is not known whether additional phosphorylation on C-terminus of ERM is related to its functions. Our data provide additional information on an Akt-dependent pathway for neuron growth regulation through radixin phosphorylation and stabilization
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