The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDNF family ligands.
Intercellular communication involves either direct cell-cell contact or release and uptake of diffusible signals, two strategies mediated by distinct and largely nonoverlapping sets of molecules. Here, we show that the neural cell adhesion molecule NCAM can function as a signaling receptor for members of the GDNF ligand family. Association of NCAM with GFRalpha1, a GPI-anchored receptor for GDNF, downregulates NCAM-mediated cell adhesion and promotes high-affinity binding of GDNF to p140(NCAM), resulting in rapid activation of cytoplasmic protein tyrosine kinases Fyn and FAK in cells lacking RET, a known GDNF signaling receptor. GDNF stimulates Schwann cell migration and axonal growth in hippocampal and cortical neurons via binding to NCAM and activation of Fyn, but independently of RET. These results uncover an unexpected intersection between short- and long-range mechanisms of intercellular communication and reveal a pathway for GDNF signaling that does not require the RET receptor.
Paratcha
Gustavo
G
Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, Retzius väg 8, A2:2, 17177, Stockholm, Sweden.
Ledda
Fernanda
F
Ibáñez
Carlos F
CF
D000818:Animals; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics; D002450:Cell Communication / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D019169:Jurkat Cells; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
C495039:GDNF protein, human; C494987:GFRA1 protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D019006:Neural Cell Adhesion Molecules; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C495001:Ret protein, rat; C494957:FYN protein, human; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C494961:Fyn protein, rat; C496050:PTK2 protein, human; D051076:Proto-Oncogene Proteins c-fyn; C496052:Ptk2 protein, rat