title: Proteolytic control of neurite outgrowth inhibitor NOGO-A by the cAMP/PKA pathway.
abstract: 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.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Maria
authors.initials: M
authors.lastname: Sepe
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Luca
authors.initials: L
authors.lastname: Lignitto
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Monia
authors.initials: M
authors.lastname: Porpora
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Rossella
authors.initials: R
authors.lastname: Delle Donne
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Laura
authors.initials: L
authors.lastname: Rinaldi
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belgianni
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Gianna
authors.initials: G
authors.lastname: Colucci
authors.affiliation: Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, University Federico II, 80131 Naples, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cuomo
authors.affiliation: Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, University Federico II, 80131 Naples, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Viggiano
authors.affiliation: Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, University Federico II, 80131 Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Scorziello
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and.
authors.forename: Corrado
authors.initials: C
authors.lastname: Garbi
authors.affiliation: Dipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, University Federico II, 80131 Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche and feliciel@unina.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Feliciello
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism*; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D000070798:Nogo Proteins; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; C000603197:Rtn4 protein, rat; D000242:Cyclic AMP; C577689:PJA2 protein, human; C094800:Pja2 protein, rat; D044767:Ubiquitin-Protein Ligases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: NOGO-A; PKA; cAMP; proteasome; ubiquitin