Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK) is the activating kinase for multiple downstream kinases, including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV), protein kinase B (PKB/Akt), and 5′AMP-kinase (AMPK), through the phosphorylation of their activation-loop Thr residues in response to increasing the intracellular Ca²⁺ concentration, as CaMKK itself is a Ca²⁺/CaM-dependent enzyme. The CaMKK-mediated kinase cascade plays important roles in a number of Ca²⁺-dependent pathways, such as neuronal morphogenesis and plasticity, transcriptional activation, autophagy, and metabolic regulation, as well as in pathophysiological pathways, including cancer progression, metabolic syndrome, and mental disorders. This review focuses on the molecular mechanism underlying CaMKK-mediated signal transduction in normal and pathophysiological conditions. We summarize the current knowledge of the structural, functional, and physiological properties of the regulatory kinase, CaMKK, and the development and application of its pharmacological inhibitors.

During neural development, endosomal trafficking controls cell shape and motility through the polarized transport of membrane proteins related to cell–cell and cell–extracellular matrix interactions. ADP ribosylation factor 6 (Arf6) is a critical small GTPase that regulates membrane trafficking between the plasma membrane and endosomes. We herein demonstrated that the knockdown of endogenous Arf6 in mouse cerebral cortices led to impaired neuronal migration in the intermediate zone and cytoplasmic retention of N-cadherin and syntaxin12 in migrating neurons. Rescue experiments with separation-of-functionArf6mutants identified Rab11 family-interacting protein 3 (FIP3)/Arfophilin-1, a dual effector for Arf6 and Rab11, as a downstream effector of Arf6 in migrating neurons. The knockdown of FIP3 led to impaired neuronal migration in the intermediate zone and cytoplasmic retention of N-cadherin in migrating neurons, similar to that of Arf6, which could be rescued by the coexpression of wild-type FIP3 but notFIP3mutants lacking the binding site for Arf6 or Rab11. These results suggest that Arf6 regulates cortical neuronal migration in the intermediate zone through the FIP3-dependent endosomal trafficking.

ADP ribosylation factor 6 (ARF6) is a member of the ARF family of small GTPases, which mediates a variety of neuronal functions accompanying the structural changes of developing and mature neurons through its regulation of actin cytoskeleton reorganization and membrane traffic. The activation of ARF6 is strictly regulated by guanine nucleotide exchange factors (GEFs). The EFA6 family is the first member that was identified to be a specific GEF for ARF6 and comprises four structurally related polypeptides (EFA6A, EFA6B, EFA6C and EFA6D). Since the cellular and subcelllular localization of GEFs is a critical determinant for the spatiotemporal activation of ARF6 in neurons, I have focused on the EFA6 family from the anatomical point of view to understand the neuronal functions of ARF6. Three members of the EFA6 family (EFA6A, EFA6C and EFA6D) are abundantly expressed in the mouse brain with distinct spatiotemporal patterns. Interestingly, they are enriched particularly in the postsynaptic density fraction, shedding light on the importance of the EFA-ARF6 pathway in neuronal synapses. Here, I will review the recent advances in the expression and functions of the EFA6 family in the nervous system.