Na,K‐ATPase β2‐subunit/AMOG as a regulator of Merlin/NF2 signaling in the cerebellum

Abstract

The Na,K‐ATPase, consisting of a catalytic α‐subunit and a regulatory β‐subunit, is a ubiquitously expressed ion pump that carries out the transport of Na+ and K+ across the plasma membranes of most animal cells. In addition to its pump function, Na,K‐ATPase serves as a signaling scaffold and a cell adhesion molecule. Of three b‐subunit isoforms, β1 is found almost in all tissues, while β2 expression is mostly restricted to brain and muscle. In cerebellar granule cells, the b2‐subunit, also known as Adhesion Molecule on Glia (AMOG), has been linked to neuron‐astrocyte adhesion and granule cell migration, suggesting its role in cerebellar development. Nevertheless, little is known about molecular pathways that link the b2‐subunit to its cellular functions. Using cerebellar granule precursor cells, we found that the β2‐subunit, but not the b1‐subunit, negatively regulates expression of a key activator of the Hippo/YAP signaling pathway, Merlin/neurofibromin‐2 (NF2). The knockout of the β2‐subunit in mice or its knockdown in cerebellar granule cell precursors resulted in increased Merlin/NF2 expression and affected down‐stream targets of Hippo signaling, i.e. increased YAP phosphorylation and decreased expression of N‐Ras. Further, the β2‐subunit knockdown altered the kinetics of Epidermal Growth Factor Receptor (EGFR) signaling in a Merlin‐dependent mode and impaired EGF‐induced reorganization of the actin cytoskeleton. Therefore, our studies for the first time provide a functional link between the Na,K‐ATPase β2‐subunit and Merlin/NF2 and suggest a role for the β2‐subunit in regulating cytoskeletal dynamics and Hippo/YAP signaling during neuronal differentiation.Support or Funding InformationThis work was supported by funds from NIGMS‐8P20GM103464, the Nemours Foundation and the DO Believe Foundation. The Biomolecular Core Lab is supported by grants NIGMS P30GM114736 (COBRE) and NIGMS‐P20GM103446 (INBRE).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.