A Functional Interaction Between Na,K-ATPase β 2 -Subunit/AMOG and NF2/Merlin Regulates Growth Factor Signaling in Cerebellar Granule Cells

• Published in: Molecular neurobiology Vol. 56; no. 11; p. 7557
• Main Authors: Litan, Alisa, Li, Zhiqin, Tokhtaeva, Elmira, Kelly, Patience, Vagin, Olga, Langhans, Sigrid A
• Format: Journal Article
• Language: English
• Published: United States 01.11.2019
• Subjects: Actin Cytoskeleton - drug effects; Actin Cytoskeleton - metabolism; Adaptor Proteins, Signal Transducing - metabolism; Animals; Cell Adhesion - drug effects; Cell Cycle Proteins - metabolism; Cell Differentiation - drug effects; Cell Line; Cerebellum - cytology; Cytoplasmic Granules - metabolism; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; ErbB Receptors - metabolism; Ion Transport - drug effects; Isoenzymes - metabolism; Mice, Inbred C57BL; Models, Biological; Monomeric GTP-Binding Proteins - metabolism; Neurofibromin 2 - metabolism; Phosphorylation - drug effects; Protein Binding - drug effects; Protein Subunits - metabolism; Signal Transduction; Sodium-Potassium-Exchanging ATPase - metabolism; Cerebellum; Epidermal growth factor; AMOG; Na,K-ATPase β2-subunit; Merlin
• ISSN: 1559-1182

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