A Functional Interaction Between Na,K-ATPase β2-Subunit/AMOG and NF2/Merlin Regulates Growth Factor Signaling in Cerebellar Granule Cells

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 the three β-subunit isoforms, β 1 is found in almost all tissues, while β 2 expression is mostly restricted to brain and muscle. In cerebellar granule cells, the β 2 -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 β 2 -subunit to its cellular functions. Using cerebellar granule precursor cells, we found that the β 2 -subunit, but not the β 1 -subunit, negatively regulates the expression of a key activator of the Hippo/YAP signaling pathway, Merlin/neurofibromin-2 (NF2). The knockdown of the β 2 -subunit resulted in increased Merlin/NF2 expression and affected downstream targets of Hippo signaling, i.e., increased YAP phosphorylation and decreased expression of N-Ras. Further, the β 2 -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 β 2 -subunit and Merlin/NF2 and suggest a role for the β 2 -subunit in regulating cytoskeletal dynamics and Hippo/YAP signaling during neuronal differentiation.