Ret oncoprotein is a functional receptor for the glial cell line-derived neurotrophic factor (GDNF) family and it is expressed in motor neurons, playing an important role in the motor neuron function. In this study, we examined the expression of the phosphorylation state of tyrosine residue 1062 (Tyr-1062) of Ret in the spinal cords of amyotrophic lateral sclerosis (ALS), using the phosphorylation state specific antibody at Tyr-1062 of Ret. The immunohistochemical study demonstrated that Tyr-1062 of Ret was phosphorylated to variable extents in the surviving motor neurons of all the ALS as well as controls studied. This is the first report that the phosphorylation of Tyr-1062 occurred in neurons with nononcogenic type of Ret. The Ret-signaling pathway by Tyr-1062 autophosphorylation is constitutively activated via the phosphatidylinositol 3-kinase and/or mitogen-activated protein kinase cascade for motoneuron survival even in the ALS motor neurons, supporting the view that GDNF is a candidate for therapeutic approach to ALS.
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