Tyrosine residue 251 is critical for M6a-induced neuroplasticity

FORMOSO, K; FRASCH, AC; SCORTICATI, C

Huerta Grande

Congreso; Reunion Anual de la SAN; 2012

SAN

Recent findings associate polymorphisms in human GPM6A with mental illnesses such as claustrophobia, schizophrenia and bipolar disorders. Neuronal glycoprotein M6a, coded by GPM6a, is involved in neuronal plasticity promoting neurite and filopodia outgrowth and, likely, synaptogenesis.   Nevertheless, the molecular basis underlying these observations remains unknown. Previously, we documented that M6a depends on membrane lipid microdomains association and activation of Src and MAPK kinases for filopodia induction. In silico analysis of phosphorylation of the tyrosine-251 at C-termini of M6a showed that it could be a target of Src kinases. Thereby, we examined whether phosphorylation/dephosphorylation at Y251 of M6a affects neurite and filopodia outgrowth and the possible targets involved in their signal propagation.  We show that phosphorylation of M6a at Y251 residue positively contributes to neurite extension in primary hippocampal neurons and N2a cells.  During this process Src and AKT are phosphorylated and recruited to the cell membrane. Expression of a non-phosphorylatable form of M6a totally arrested neurite outgrowth. At difference with neurites extension, phosphorylation/dephosphorylation of Y251 has no effect on M6a stimulated filopodia formation in neurons and COS-7 cells. Although, PI3K inhibitors, LY294002 and wotmannin, dramatically blocked filopodia induction in M6a-overexpresing neurons. The Ras family of GTPases is not involved in neurite extension neither filopodia induction promoted by M6a.  We suggest that phosphorylation of M6a at tyrosine 251 is critical for a specific stage of neuronal development and triggers redundant intracellular signaling pathways such as Src and PI3K/AKT leads neurite extension.