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Vol. 17, Issue 12, 5141-5152, December 2006

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Phosphoprotein Enriched in Astrocytes-15 kDa Expression Inhibits Astrocyte Migration by a Protein Kinase C-dependent Mechanism

François Renault-Mihara^*, Frédéric Beuvon, Xavier Iturrioz, Brigitte Canton^*, Sophie De Bouard, Nadine Léonard, Shahul Mouhamad^||, Ariane Sharif^*, Joe W. Ramos^¶, Marie-Pierre Junier^*, and Hervé Chneiweiss^*

*Institut National de la Santé et de la Recherche Médicale U752, Collège de France, 75005 Paris, France; Department of Pathology-Neurooncology, Hopital Sainte-Anne, 75674, Paris Cedex 14, France; Institut National de la Santé et de la Recherche Médicale U691, Collège de France, 75005 Paris, France; Institut National de la Santé et de la Recherche Médicale U421, Faculté de Médecine, 94010 Creteil, France; ^||Institut National de la Santé et de la Recherche Médicale U542, Hopital Paul Brousse, 94807 Villejuif Cedex, France; and ^¶Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, HI 96813

Submitted November 22, 2005; Revised August 31, 2006; Accepted September 7, 2006
Monitoring Editor: Anne Ridley

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, Gö6976, and rottlerin, and chronic application of phorbol 12-myristate 13-acetate and/or bryostatin-1 indicated that PKC mediated PEA-15 inhibition of astrocyte migration. PEA-15–/– astrocytes constitutively expressed a 40-kDa form of PKC 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-dependent pathway involving the constitutive expression of a catalytic fragment of PKC.

Address correspondence to: Hervé Chneiweiss (herve.chneiweiss{at}college-de-france.fr)

Abbreviations used: CaMKII, calcium/calmodulin-dependent protein kinase II; CF-PKC, catalytic fragment of protein kinase C; ERK, extracellular signal-regulated kinase; GST, glutathione S-transferase; MAPK, mitogen-activated protein kinase; MLC, myosin light chain; PEA-15, phosphoprotein enriched in astrocytes-15 kDa; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PMA, phorbol 12-myristate 13-acetate; PTD, protein transducer domain; TGF, transforming growth factor

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