Tyrosine 251 at the C-terminus of Neuronal Glycoprotein M6a is Critical for Neurite Outgrowth

KARINA FORMOSO; ALBERTO CC FRASCH; CAMILA SCORTICATI

Congreso; XXVIII Congreso de la Sociedad Argentina de Investigación en Neurociencias; 2013

Sociedad Argentina de Investigación en Neurociencias

Recent findings associate polymorphisms in human GPM6A with mental illnesses such as claustrophobia, schizophrenia and bipolar disorders. Neuronal glycoprotein M6a is involved in neuronal plasticity promoting neurite and filopodia outgrowth and synaptogenesis. Nevertheless, the molecular bases underlying these observations remain unknown. Previously, we documented that M6a depends on the association of membrane lipid microdomains and activation of Src and MAPK kinases for filopodia induction. In silico analysis of phosphorylation of the tyrosine-251 at the C-terminus of M6a showed that it could be a target of Src kinases. We examined whether phosphorylation at Y251 of M6a affects neurite and filopodia outgrowth and the targets involved in their signal propagation. We found that phosphorylation of Y251 contributes to neurite extension in hippocampal neurons and N2a cells. In  addition, Src and AKT are phosphorylated and recruited to the cell membrane.Expression of a non-phosphorylatable form of M6a arrested neurite outgrowth. In contrast, phosphorylation state had no effect on M6a-stimulated filopodia formation. PI3K inhibitors dramatically blocked filopodia induction in M6a-overexpresing neurons. We suggest that phosphorylation of M6a at Y251 is critical for a specific stage of neuronal development and triggers redundant signaling pathways such as Src and PI3K/AKT, leading to neurite extension.