Neogenin regulates neuronal survival through DAP kinase.
The repulsive guidance molecule (RGM) is a membrane-bound protein that has diverse functions in the developing central nervous system. Identification of neogenin as a receptor for RGM provided evidence of its cell death-inducing activity in the absence of RGM. Here, we show that the serine/threonine kinase death-associated protein kinase (DAPK) is involved in the signal transduction of neogenin. Neogenin interacts with DAPK and reduces DAPK autophosphorylation on Ser308 in vitro. Neogenin-induced cell death is abolished in the presence of RGM or by blocking DAPK. Although neogenin overexpression or RGM downregulation in the chick neural tube in vivo induces apoptosis, coexpression of the dominant-negative mutant or small-interference RNA of DAPK attenuates this proapoptotic activity. Thus, RGM/neogenin regulates cell fate by controlling the DAPK activity.
Fujita
Y
Y
Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Taniguchi
J
J
Uchikawa
M
M
Endo
M
M
Hata
K
K
Kubo
T
T
Mueller
B K
BK
Yamashita
T
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D002642:Chick Embryo; D045304:Cytochromes c / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D058851:GPI-Linked Proteins; D020868:Gene Silencing; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D054259:Neural Tube / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques
D051017:Apoptosis Regulatory Proteins; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C502259:RGM protein, rat; D011993:Recombinant Fusion Proteins; C091279:neogenin; D045304:Cytochromes c; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases