LINGO-1 Interacts with WNK1 to Regulate Nogo-induced Inhibition of Neurite Extension

Abstract

LINGO-1 is a component of the tripartite receptor complexes, which act as a convergent mediator of the intracellular signaling in response to myelin-associated inhibitors and lead to collapse of growth cone and inhibition of neurite extension. Although the function of LINGO-1 has been intensively studied, its downstream signaling remains elusive. In the present study, a novel interaction between LINGO-1 and a serine-threonine kinase WNK1 was identified by yeast two-hybrid screen. The interaction was further validated by fluorescence resonance energy transfer and co-immunoprecipitation, and this interaction was intensified by Nogo66 treatment. Morphological evidences showed that WNK1 and LINGO-1 were co-localized in cortical neurons. Furthermore, either suppressing WNK1 expression by RNA interference or overexpression of WNK1-(123-510) attenuated Nogo66-induced inhibition of neurite extension and inhibited the activation of RhoA. Moreover, WNK1 was identified to interact with Rho-GDI1, and this interaction was attenuated by Nogo66 treatment, further indicating its regulatory effect on RhoA activation. Taken together, our results suggest that WNK1 is a novel signaling molecule involved in regulation of LINGO-1 mediated inhibition of neurite extension.

Neurotrophin receptors: Old friends with new partners

“…Kalirin9, a Rho GTP exchange factor (Rho GEF) that binds p75 NTR in competition with RhoGDI also is implicated in p75 NTR -dependent RhoA activation (Harrington et al, 2008). MAIF-dependent repellant effects on axon growth are dependent on WNK-1, a serine protein kinase that binds LINGO-1 and RhoGDI (Zhang et al, 2009). A detailed mechanism for the functional cooperation of p75 NTR /Troy, NgR, LINGO1, Rho-GDI, Wnk-1 and kalirin9 remains to be defined.…”

Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats

“…Altogether, the activation of this trimolecular receptor complex sets up a signaling cascade leading to growth cone collapse, preventing further axonal growth and inhibiting myelination 18,24 . Additional signaling co-factors such as With No Lysine K (WNK1) 25 , Myelin transcription factor 1 (Myt1) and its homolog Myt1-like (Myt1l) are known to be associated with Lingo-1 signaling due to a lack of p75 and TROY receptors on Lingo-1 expressing neurons 26,27 . Genetic associations with schizophrenia have been previously reported for the Myt1l gene in different populations 28,29 , and the knockdown of Myt1 has been shown to induce apoptosis 30 , strengthening the relevance of studying this Lingo-1 cofactor in a neurodevelopmental PCP induced model for schizophrenia.…”

LINGO-1 Receptor Promotes Neuronal Apoptosis by Inhibiting WNK3 Kinase Activity

“…However, neither knockdown nor overexpression of WNK1 had any effect on neuronal survival, indicating that WNK1 is not involved in the regulation of neuronal apoptosis (5). Among the four known WNK family members, only WNK3 has been reported to regulate cell survival (17).…”

“…LINGO-1 is expressed in neurons, oligodendrocytes, and a subset of reactive hypertrophic astrocytes (6 -8). In neurons, it is involved in mediating growth cone collapse and inhibiting neurite extension (1,2,5). LINGO-1 also plays an important role in the inhibition of oligodendrocyte differentiation and myelination (6,7,9).…”

“…The extracellular domain of LINGO-1 associates with itself to form ring-like tetramers that are thought to serve as a scaffold to facilitate the assembly of the receptor complex (3). The intracellular tail contains a canonical EGF receptor (EGFR) 3 -like tyrosine phosphorylation site (residue 591) that is critical for intracellular signaling (4,5). LINGO-1 is expressed in neurons, oligodendrocytes, and a subset of reactive hypertrophic astrocytes (6 -8).…”