title: LINGO-1 receptor promotes neuronal apoptosis by inhibiting WNK3 kinase activity.
abstract: LINGO-1 is a functional component of the Nogo receptor 1 · p75(NTR) · LINGO-1 and Nogo receptor 1 · TAJ (TNFRSF19/TROY)·LINGO-1 signaling complexes. It has recently been shown that LINGO-1 antagonists significantly improve neuronal survival after neural injury. However, the mechanism by which LINGO-1 signaling influences susceptibility to apoptosis remains unknown. In an effort to better understand how LINGO-1 regulates these signaling pathways, we used an established model of serum deprivation (SD) to induce neuronal apoptosis. We demonstrate that treatment either with a construct containing the intracellular domain of LINGO-1 or with Nogo66, a LINGO-1 receptor complex agonist, resulted in an enhanced rate of apoptosis in primary cultured cortical neurons under SD. Reducing the expression levels of the serine/threonine kinase WNK3 using shRNA or inhibiting its kinase activity had similar effects on the survival of serum-deprived neurons. Consistent with these observations, we found that LINGO-1 and WNK3 co-localized and co-precipitated in cultured cortical neurons and brain tissue. Significantly, this co-association was enhanced by Nogo66 treatment. Binding of WNK3 to the intracellular domain of LINGO-1 led to a reduction in WNK3 kinase activity, as did Nogo66 stimulation. Moreover, in vitro and in vivo evidence indicates that endogenous WNK3 suppresses SD-induced neuronal apoptosis in a kinase-dependent manner, as the expression of either a WNK3 RNAi construct or a kinase-dead N-terminal fragment of WNK3 led to increased apoptosis. Taken together, our results show that LINGO-1 potentiates neuronal apoptosis, likely by inhibiting WNK3 kinase activity.
authors.affiliation: Institute of Neuroscience and MOE Key Laboratory of Molecular Neurobiology, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhaohuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Xiang
authors.forename: Zhongwang
authors.initials: Z
authors.lastname: Yu
authors.forename: Jifeng
authors.initials: J
authors.lastname: Feng
authors.forename: Cheng
authors.initials: C
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D000070798:Nogo Proteins; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C482293:LINGO1 protein, human; C525164:LINGO1 protein, rat; D008565:Membrane Proteins; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; C000603197:Rtn4 protein, rat; D011494:Protein Kinases; C547645:Wnk3 protein, rat; D017346:Protein Serine-Threonine Kinases; C488586:WNK3 protein, human