The intracellular domain of L1CAM binds to casein kinase 2α and is neuroprotective via inhibition of the tumor suppressors PTEN and p53.
Cell adhesion molecule L1 promotes neuritogenesis and neuronal survival through triggering MAPK pathways. Based on the findings that L1 is associated with casein kinase 2 (CK2), and that deficiency in PTEN promotes neuritogenesis in vitro and regeneration after trauma, we examined the functional relationship between L1 and PTEN. In parallel, we investigated the tumor suppressor p53, which also regulates neuritogenesis. Here, we report that the intracellular domain of L1 binds to the subunit CK2α, and that knockdown of L1 leads to CK2 dephosphorylation and an increase in PTEN and p53 levels. Overexpression of L1, but not the L1 mutants L1 (S1181N, E1184V), which reduced binding between L1 and CK2, reduced expression levels of PTEN and p53 proteins, and enhanced levels of phosphorylated CK2α and mammalian target of rapamycin, which is a downstream effector of PTEN and p53. Treatment of neurons with a CK2 inhibitor or transfection with CK2α siRNA increased levels of PTEN and p53, and inhibited neuritogenesis. The combined observations indicate that L1 downregulates expression of PTEN and p53 via direct binding to CK2α. We suggest that L1 stimulates neuritogenesis by activating CK2α leading to decreased levels of PTEN and p53 via a novel, L1-triggered and CK2α-mediated signal transduction pathway. L1CAM (L1 cell adhesion molecule) is implicated in neural functions through the cognate src/MAP kinase signaling pathway. We now describe a novel signaling platform operating via the alpha subunit of casein kinase 2 which binds to the intracellular domain of L1. Knockdown of L1CAM leads to increased levels of tumor suppressor PTEN (phosphatase and tensin homolog) and p53, known to inhibit neuritogenesis in vitro and recovery from trauma in vivo. By activating this enzyme, L1CAM adds to its beneficial functions by decreasing the levels of PTEN and p53.
Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong, China.
Yan
Y
Wang
Center for Neuroscience, Shantou University Medical College, Shantou, Guangdong, China.
Melitta
M
Schachner
D000818:Animals; D015153:Blotting, Western; D047390:Casein Kinase II / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D009416:Nerve Regeneration / Q000502:physiology; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D039842:Neural Cell Adhesion Molecule L1; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D047390:Casein Kinase II; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
L1; PTEN; casein kinase 2; neurite outgrowth; neuronal survival; p53