Nesca, a novel adapter, translocates to the nuclear envelope and regulates neurotrophin-induced neurite outgrowth.
We provide the first characterization of a novel signaling adapter, Nesca, in neurotrophic signal transduction. Nesca contains a RUN domain, a WW domain, a leucine zipper, a carboxyl-terminal SH3 domain, and several proline-rich regions. Nesca is highly expressed in the brain, is serine phosphorylated, and mobilizes from the cytoplasm to the nuclear membrane in response to neurotrophin, but not epidermal growth factor, stimulation in a MEK-dependent process. Overexpression studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent neurite outgrowth at nonsaturating doses of nerve growth factor (NGF). Similarly, short interfering RNA studies significantly reduce NGF-dependent neuritogenesis in PC12 cells. Mutational analyses demonstrate that the RUN domain is an important structural determinant for the nuclear translocation of Nesca and that the nuclear redistribution of Nesca is essential to its neurite outgrowth-promoting properties. Collectively, these works provide the first functional characterization of Nesca in the context of neurotrophin signaling and suggest that Nesca serves a novel, nuclear-dependent role in neurotrophin-dependent neurite outgrowth.
MacDonald
James I S
JI
Laboratory of Neural Signalling, Cell Biology Group, The Robarts Research Institute, 100 Perth Dr., London, Ontario, N6A 5K8 Canada.
Kubu
Chris J
CJ
Meakin
Susan O
SO
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D019913:Nuclear Localization Signals; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D009414:Nerve Growth Factors; D019913:Nuclear Localization Signals; C410103:RUSC1 protein, human; D011993:Recombinant Fusion Proteins; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases