TY - JOUR
T1 - Proteolytic control of neurite outgrowth inhibitor NOGO-A by the cAMP/PKA pathway
AU - Sepe, Maria
AU - Lignitto, Luca
AU - Porpora, Monia
AU - Donne, Rossella Delle
AU - Rinaldi, Laura
AU - Belgianni, Giuseppe
AU - Colucci, Gianna
AU - Cuomo, Ornella
AU - Viggiano, Davide
AU - Scorziello, Antonella
AU - Garbi, Corrado
AU - Annunziato, Lucio
AU - Feliciello, Antonio
PY - 2014/11/4
Y1 - 2014/11/4
N2 - Protein kinase A (PKA) controls major aspects of neurite outgrowth and morphogenesis and plays an essential role in synaptic plasticity and memory. However, the molecular mechanism(s) of PKA action on neurite sprouting and activity are still unknown. Here, we report that in response to neurotrophin or cAMP stimulation the RING ligase praja2 ubiquitinates and degrades NOGO-A, a major inhibitor of neurite outgrowth in mammalian brain. Genetic silencing of praja2 severely inhibited neurite extension of differentiating neuroblastoma cells and mesencephalic neurons and axon outgrowth and sprouting of striatal terminals in developing rat brain. This phenotype was rescued when both praja2 and NOGO-A were depleted, suggesting that NOGO-A is, indeed, a biologically relevant target of praja2 in neuronal cells. Our findings unveil a novel mechanism that functionally couples cAMP signaling with the proteolytic turnover of NOGO-A, positively impacting on neurite outgrowth in mammalian brain.
AB - Protein kinase A (PKA) controls major aspects of neurite outgrowth and morphogenesis and plays an essential role in synaptic plasticity and memory. However, the molecular mechanism(s) of PKA action on neurite sprouting and activity are still unknown. Here, we report that in response to neurotrophin or cAMP stimulation the RING ligase praja2 ubiquitinates and degrades NOGO-A, a major inhibitor of neurite outgrowth in mammalian brain. Genetic silencing of praja2 severely inhibited neurite extension of differentiating neuroblastoma cells and mesencephalic neurons and axon outgrowth and sprouting of striatal terminals in developing rat brain. This phenotype was rescued when both praja2 and NOGO-A were depleted, suggesting that NOGO-A is, indeed, a biologically relevant target of praja2 in neuronal cells. Our findings unveil a novel mechanism that functionally couples cAMP signaling with the proteolytic turnover of NOGO-A, positively impacting on neurite outgrowth in mammalian brain.
KW - CAMP
KW - NOGO-A
KW - PKA
KW - Proteasome
KW - Ubiquitin
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UR - http://www.scopus.com/inward/citedby.url?scp=84914706588&partnerID=8YFLogxK
U2 - 10.1073/pnas.1410274111
DO - 10.1073/pnas.1410274111
M3 - Article
C2 - 25331889
AN - SCOPUS:84914706588
VL - 111
SP - 15729
EP - 15734
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
ER -