Phosphoprotein enriched in astrocytes-15 kDa expression inhibits astrocyte migration by a protein kinase C delta-dependent mechanism |
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Authors: | Renault-Mihara François Beuvon Frédéric Iturrioz Xavier Canton Brigitte De Bouard Sophie Léonard Nadine Mouhamad Shahul Sharif Ariane Ramos Joe W Junier Marie-Pierre Chneiweiss Hervé |
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Institution: | Institut National de la Santé et de la Recherche Médicale U752, Collège de France, 75005 Paris, France. |
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Abstract: | Phosphoprotein enriched in astrocytes-15 kDa (PEA-15), a phosphoprotein enriched in astrocytes, inhibits both apoptosis and proliferation in normal and cancerous cells. Here, analysis of PEA-15 expression in glioblastoma organotypic cultures revealed low levels of PEA-15 in tumor cells migrating away from the explants, regardless of the expression levels in the originating explants. Because glioblastomas are highly invasive primary brain tumors that can originate from astrocytes, we explored the involvement of PEA-15 in the control of astrocyte migration. PEA-15-/- astrocytes presented an enhanced motility in vitro compared with their wild-type counterparts. Accordingly, NIH-3T3 cells transfected by green fluorescent protein-PEA-15 displayed a reduced migration. Reexpression of PEA-15 restored PEA-15-/- astrocyte motility to wild-type levels. Pharmacological manipulations excluded a participation of extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt, and calcium/calmodulin-dependent protein kinase II in this effect of PEA-15. In contrast, treatment by bisindolylmaleimide, G?6976, and rottlerin, and chronic application of phorbol 12-myristate 13-acetate and/or bryostatin-1 indicated that PKC delta mediated PEA-15 inhibition of astrocyte migration. PEA-15-/- astrocytes constitutively expressed a 40-kDa form of PKC delta that was down-regulated upon PEA-15 reexpression. Together, these data reveal a new function for PEA-15 in the inhibitory control of astrocyte motility through a PKC delta-dependent pathway involving the constitutive expression of a catalytic fragment of PKC delta. |
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