LINGO-1 interacts with WNK1 to regulate nogo-induced inhibition of neurite extension.
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.
Zhang
Zhaohuan
Z
Institute of Neuroscience and Key Laboratory of Molecular Neurobiology, Ministry of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
Xu
Xiaohui
X
Zhang
Yong
Y
Zhou
Jianfeng
J
Yu
Zhongwang
Z
He
Cheng
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000502:physiology; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D031541:Fluorescence Resonance Energy Transfer; D015723:Gene Library; D005822:Genetic Vectors; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000737:chemistry / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000076204:WNK Lysine-Deficient Protein Kinase 1
D017931:DNA Primers; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; C482293:LINGO1 protein, human; D008164:Luminescent Proteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human