Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Cell Biol. 169 (2): 341-354

Copyright © 2005 by the Rockefeller University Press.


Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth

Antonella Santuccione1,2, Vladimir Sytnyk1, Iryna Leshchyns'ka1, , and Melitta Schachner1

1 Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany
2 Department of Oncology and Neuroscience, Gabriele d'Annunzio University, 66100 Chieti, Italy

Correspondence to Melitta Schachner: melitta.schachner{at}

Abstract: In spite of advances in understanding the role of the cellular prion protein (PrP) in neural cell interactions, the mechanisms of PrP function remain poorly characterized. We show that PrP interacts directly with the neural cell adhesion molecule (NCAM) and associates with NCAM at the neuronal cell surface. Both cis and trans interactions between NCAM at the neuronal surface and PrP promote recruitment of NCAM to lipid rafts and thereby regulate activation of fyn kinase, an enzyme involved in NCAM-mediated signaling. Cis and trans interactions between NCAM and PrP promote neurite outgrowth. When these interactions are disrupted in NCAM-deficient and PrP-deficient neurons or by PrP antibodies, NCAM/PrP-dependent neurite outgrowth is arrested, indicating that PrP is involved in nervous system development cooperating with NCAM as a signaling receptor.

A. Santuccione, V. Sytnyk, and I. Leshchyns'ka contributed equally to this paper.

Abbreviations used in this paper: GPI, glycosylphosphatidylinositol; NCAM, neural cell adhesion molecule; PrP, prion protein; PSA, polysialic acid; RPTP{alpha}, receptor type protein phosphatase {alpha}.

Prion protein and cancers.
X. Yang, Y. Zhang, L. Zhang, T. He, J. Zhang, and C. Li (2014)
Acta Biochim Biophys Sin
   Abstract »    Full Text »    PDF »
The Prion Protein Modulates A-type K+ Currents Mediated by Kv4.2 Complexes through Dipeptidyl Aminopeptidase-like Protein 6.
R. C. C. Mercer, L. Ma, J. C. Watts, R. Strome, S. Wohlgemuth, J. Yang, N. R. Cashman, M. B. Coulthart, G. Schmitt-Ulms, J. H. Jhamandas, et al. (2013)
J. Biol. Chem. 288, 37241-37255
   Abstract »    Full Text »    PDF »
A lipid storage-like disorder contributes to cognitive decline in HIV-infected subjects.
V. V. R. Bandaru, M. M. Mielke, N. Sacktor, J. C. McArthur, I. Grant, S. Letendre, L. Chang, V. Wojna, C. Pardo, P. Calabresi, et al. (2013)
Neurology 81, 1492-1499
   Abstract »    Full Text »    PDF »
The Neural Cell Adhesion Molecule Promotes Maturation of the Presynaptic Endocytotic Machinery by Switching Synaptic Vesicle Recycling from Adaptor Protein 3 (AP-3)- to AP-2-Dependent Mechanisms.
A. Shetty, V. Sytnyk, I. Leshchyns'ka, D. Puchkov, V. Haucke, and M. Schachner (2013)
J. Neurosci. 33, 16828-16845
   Abstract »    Full Text »    PDF »
The Neural Cell Adhesion Molecule (NCAM) Associates with and Signals through p21-Activated Kinase 1 (Pak1).
S. Li, I. Leshchyns'ka, Y. Chernyshova, M. Schachner, and V. Sytnyk (2013)
J. Neurosci. 33, 790-803
   Abstract »    Full Text »    PDF »
Polysialylated NCAM and EphrinA/EphA Regulate Synaptic Development of GABAergic Interneurons in Prefrontal Cortex.
L. H. Brennaman, X. Zhang, H. Guan, J. W. Triplett, A. Brown, G. P. Demyanenko, P. B. Manis, L. Landmesser, and P. F. Maness (2013)
Cereb Cortex 23, 162-177
   Abstract »    Full Text »    PDF »
Neuritogenesis: the prion protein controls {beta}1 integrin signaling activity.
D. Loubet, C. Dakowski, M. Pietri, E. Pradines, S. Bernard, J. Callebert, H. Ardila-Osorio, S. Mouillet-Richard, J.-M. Launay, O. Kellermann, et al. (2012)
FASEB J 26, 678-690
   Abstract »    Full Text »    PDF »
A system-level approach for deciphering the transcriptional response to prion infection.
M. Zampieri, G. Legname, D. Segre, and C. Altafini (2011)
Bioinformatics 27, 3407-3414
   Abstract »    Full Text »    PDF »
Prion Protein Promotes Growth Cone Development through Reggie/Flotillin-Dependent N-Cadherin Trafficking.
V. Bodrikov, G. P. Solis, and C. A. O. Stuermer (2011)
J. Neurosci. 31, 18013-18025
   Abstract »    Full Text »    PDF »
Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding.
P. Carulla, A. Bribian, A. Rangel, R. Gavin, I. Ferrer, C. Caelles, J. A. del Rio, and F. Llorens (2011)
Mol. Biol. Cell 22, 3041-3054
   Abstract »    Full Text »    PDF »
Developmental influence of the cellular prion protein on the gene expression profile in mouse hippocampus.
S. Benvegnu, P. Roncaglia, F. Agostini, C. Casalone, C. Corona, S. Gustincich, and G. Legname (2011)
Physiol Genomics 43, 711-725
   Abstract »    Full Text »    PDF »
The Neural Cell Adhesion Molecule Promotes FGFR-Dependent Phosphorylation and Membrane Targeting of the Exocyst Complex to Induce Exocytosis in Growth Cones.
Y. Chernyshova, I. Leshchyns'ka, S.-C. Hsu, M. Schachner, and V. Sytnyk (2011)
J. Neurosci. 31, 3522-3535
   Abstract »    Full Text »    PDF »
Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin {gamma}1 chain.
F. H. Beraldo, C. P. Arantes, T. G. Santos, C. F. Machado, M. Roffe, G. N. Hajj, K. S. Lee, A. C. Magalhaes, F. A. Caetano, G. L. Mancini, et al. (2011)
FASEB J 25, 265-279
   Abstract »    Full Text »    PDF »
Clustering of the Neural Cell Adhesion Molecule (NCAM) at the Neuronal Cell Surface Induces Caspase-8- and -3-dependent Changes of the Spectrin Meshwork Required for NCAM-mediated Neurite Outgrowth.
D. Westphal, V. Sytnyk, M. Schachner, and I. Leshchyns'ka (2010)
J. Biol. Chem. 285, 42046-42057
   Abstract »    Full Text »    PDF »
Role of {alpha}7 Nicotinic Acetylcholine Receptor in Calcium Signaling Induced by Prion Protein Interaction with Stress-inducible Protein 1.
F. H. Beraldo, C. P. Arantes, T. G. Santos, N. G. T. Queiroz, K. Young, R. J. Rylett, R. P. Markus, M. A. M. Prado, and V. R. Martins (2010)
J. Biol. Chem. 285, 36542-36550
   Abstract »    Full Text »    PDF »
Cellular Prion Protein Promotes Regeneration of Adult Muscle Tissue.
R. Stella, M. L. Massimino, M. Sandri, M. C. Sorgato, and A. Bertoli (2010)
Mol. Cell. Biol. 30, 4864-4876
   Abstract »    Full Text »    PDF »
Cellular Form of Prion Protein Inhibits Reelin-Mediated Shedding of Caspr from the Neuronal Cell Surface to Potentiate Caspr-Mediated Inhibition of Neurite Outgrowth.
V. Devanathan, I. Jakovcevski, A. Santuccione, S. Li, H. J. Lee, E. Peles, I. Leshchyns'ka, V. Sytnyk, and M. Schachner (2010)
J. Neurosci. 30, 9292-9305
   Abstract »    Full Text »    PDF »
Synthetic amyloid-{beta} oligomers impair long-term memory independently of cellular prion protein.
C. Balducci, M. Beeg, M. Stravalaci, A. Bastone, A. Sclip, E. Biasini, L. Tapella, L. Colombo, C. Manzoni, T. Borsello, et al. (2010)
PNAS 107, 2295-2300
   Abstract »    Full Text »    PDF »
Reciprocal remodeling upon binding of the prion protein to its signaling partner hop/STI1.
S. A. Romano, Y. Cordeiro, L. M. T. R. Lima, M. H. Lopes, J. L. Silva, D. Foguel, and R. Linden (2009)
FASEB J 23, 4308-4316
   Abstract »    Full Text »    PDF »
Analysis of Non-canonical Fibroblast Growth Factor Receptor 1 (FGFR1) Interaction Reveals Regulatory and Activating Domains of Neurofascin.
K. Kirschbaum, M. Kriebel, E. U. Kranz, O. Potz, and H. Volkmer (2009)
J. Biol. Chem. 284, 28533-28542
   Abstract »    Full Text »    PDF »
Natural and synthetic prion structure from X-ray fiber diffraction.
H. Wille, W. Bian, M. McDonald, A. Kendall, D. W. Colby, L. Bloch, J. Ollesch, A. L. Borovinskiy, F. E. Cohen, S. B. Prusiner, et al. (2009)
PNAS 106, 16990-16995
   Abstract »    Full Text »    PDF »
p53-Dependent Transcriptional Control of Cellular Prion by Presenilins.
B. Vincent, C. Sunyach, H.-D. Orzechowski, P. St George-Hyslop, and F. Checler (2009)
J. Neurosci. 29, 6752-6760
   Abstract »    Full Text »    PDF »
Ethanol inhibits neuronal differentiation by disrupting activity-dependent neuroprotective protein signaling.
S. Chen and M. E. Charness (2008)
PNAS 105, 19962-19967
   Abstract »    Full Text »    PDF »
Cryo-Immunogold Electron Microscopy for Prions: Toward Identification of a Conversion Site.
S. F. Godsave, H. Wille, P. Kujala, D. Latawiec, S. J. DeArmond, A. Serban, S. B. Prusiner, and P. J. Peters (2008)
J. Neurosci. 28, 12489-12499
   Abstract »    Full Text »    PDF »
NCAM induces CaMKII{alpha}-mediated RPTP{alpha} phosphorylation to enhance its catalytic activity and neurite outgrowth.
V. Bodrikov, V. Sytnyk, I. Leshchyns'ka, J. den Hertog, and M. Schachner (2008)
J. Cell Biol. 182, 1185-1200
   Abstract »    Full Text »    PDF »
Dominant-negative Effects of the N-terminal Half of Prion Protein on Neurotoxicity of Prion Protein-like Protein/Doppel in Mice.
D. Yoshikawa, N. Yamaguchi, D. Ishibashi, H. Yamanaka, N. Okimura, Y. Yamaguchi, T. Mori, H. Miyata, K. Shigematsu, S. Katamine, et al. (2008)
J. Biol. Chem. 283, 24202-24211
   Abstract »    Full Text »    PDF »
Genes contributing to prion pathogenesis.
G. Tamguney, K. Giles, D. V. Glidden, P. Lessard, H. Wille, P. Tremblay, D. F. Groth, F. Yehiely, C. Korth, R. C. Moore, et al. (2008)
J. Gen. Virol. 89, 1777-1788
   Abstract »    Full Text »    PDF »
Endocytosis of Prion Protein Is Required for ERK1/2 Signaling Induced by Stress-Inducible Protein 1.
F. A. Caetano, M. H. Lopes, G. N. M. Hajj, C. F. Machado, C. Pinto Arantes, A. C. Magalhaes, M. D. P. B. Vieira, T. A. Americo, A. R. Massensini, S. A. Priola, et al. (2008)
J. Neurosci. 28, 6691-6702
   Abstract »    Full Text »    PDF »
Physiology of the Prion Protein.
R. Linden, V. R. Martins, M. A. M. Prado, M. Cammarota, I. Izquierdo, and R. R. Brentani (2008)
Physiol Rev 88, 673-728
   Abstract »    Full Text »    PDF »
Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein.
K. S. Lee, L. D. Raymond, B. Schoen, G. J. Raymond, L. Kett, R. A. Moore, L. M. Johnson, L. Taubner, J. O. Speare, H. A. Onwubiko, et al. (2007)
J. Biol. Chem. 282, 36525-36533
   Abstract »    Full Text »    PDF »
Prion Protein Regulates Glutamate-Dependent Lactate Transport of Astrocytes.
R. Kleene, G. Loers, J. Langer, Y. Frobert, F. Buck, and M. Schachner (2007)
J. Neurosci. 27, 12331-12340
   Abstract »    Full Text »    PDF »
Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion.
O. Nicolas, R. Gavin, N. Braun, J. M. Urena, X. Fontana, E. Soriano, A. Aguzzi, and J. Antonio del Rio (2007)
FASEB J 21, 3107-3117
   Abstract »    Full Text »    PDF »
Cellular prion protein interaction with vitronectin supports axonal growth and is compensated by integrins.
G. N. M. Hajj, M. H. Lopes, A. F. Mercadante, S. S. Veiga, R. B. da Silveira, T. G. Santos, K. C. B. Ribeiro, M. A. Juliano, S. G. Jacchieri, S. M. Zanata, et al. (2007)
J. Cell Sci. 120, 1915-1926
   Abstract »    Full Text »    PDF »
The C-terminal Products of Cellular Prion Protein Processing, C1 and C2, Exert Distinct Influence on p53-dependent Staurosporine-induced Caspase-3 Activation.
C. Sunyach, M. A. Cisse, C. A. da Costa, B. Vincent, and F. Checler (2007)
J. Biol. Chem. 282, 1956-1963
   Abstract »    Full Text »    PDF »
BAD-LAMP defines a subset of early endocytic organelles in subpopulations of cortical projection neurons.
A. David, M.-C. Tiveron, A. Defays, C. Beclin, V. Camosseto, E. Gatti, H. Cremer, and P. Pierre (2007)
J. Cell Sci. 120, 353-365
   Abstract »    Full Text »    PDF »
Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes.
G. Legname, H.-O. B. Nguyen, D. Peretz, F. E. Cohen, S. J. DeArmond, and S. B. Prusiner (2006)
PNAS 103, 19105-19110
   Abstract »    Full Text »    PDF »
NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex.
V. Sytnyk, I. Leshchyns'ka, A. G. Nikonenko, and M. Schachner (2006)
J. Cell Biol. 174, 1071-1085
   Abstract »    Full Text »    PDF »
Amyloid Fibrils of Mammalian Prion Protein Are Highly Toxic to Cultured Cells and Primary Neurons.
V. Novitskaya, O. V. Bocharova, I. Bronstein, and I. V. Baskakov (2006)
J. Biol. Chem. 281, 13828-13836
   Abstract »    Full Text »    PDF »
Prion 2005: Between Fundamentals and Society's Needs.
C. Treiber (2006)
Sci. Aging Knowl. Environ. 2006, pe4
   Abstract »    Full Text »
Interaction of Cellular Prion and Stress-Inducible Protein 1 Promotes Neuritogenesis and Neuroprotection by Distinct Signaling Pathways.
M. H. Lopes, G. N. M. Hajj, A. G. Muras, G. L. Mancini, R. M. P. S. Castro, K. C. B. Ribeiro, R. R. Brentani, R. Linden, and V. R. Martins (2005)
J. Neurosci. 25, 11330-11339
   Abstract »    Full Text »    PDF »
Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis.
D. R. Taylor, N. T. Watt, W. S. S. Perera, and N. M. Hooper (2005)
J. Cell Sci. 118, 5141-5153
   Abstract »    Full Text »    PDF »
Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease.
J. Chin, J. J. Palop, J. Puolivali, C. Massaro, N. Bien-Ly, H. Gerstein, K. Scearce-Levie, E. Masliah, and L. Mucke (2005)
J. Neurosci. 25, 9694-9703
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882