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J. Biol. Chem., Vol. 279, Issue 47, 48808-48816, November 19, 2004

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ErbB4 Expression in Neural Progenitor Cells (ST14A) Is Necessary to Mediate Neuregulin-11-induced Migration^*

Giovanna Gambarotta, Donatella Garzotto¶, Erika Destro¶, Beatrice Mautino, Costanza Giampietro, Santina Cutrupi||, Claudio Dati, Elena Cattaneo**, Aldo Fasolo, and Isabelle Perroteau

From the Department of Human and Animal Biology, University of Torino, Torino 10123, Italy, the ^||Department of Medical Sciences, University of Piemonte Orientale, Novara 28100, Italy, and the ^**Department of Pharmacological Sciences, University of Milan, Milan 20133, Italy

Activation of the receptor tyrosine kinase ErbB4 leads to various cellular responses such as proliferation, survival, differentiation, and chemotaxis. Two pairs of naturally occurring ErbB4 isoforms differing in their juxtamembrane (JMa/JMb) and C termini (cyt1/cyt2) have been described. To examine the role of ErbB4 in neuron migration, we cloned and stably transfected each of the four ErbB4 isoforms in ST14A cells (a neural progenitor cell line derived from the striatum of embryonic day 14 rats) endogenously expressing the other members of the ErbB family: ErbB1, ErbB2, and ErbB3. Using immunoprecipitation assays, we showed that the neuregulin-11 (NRG11) stimulus induced ErbB4 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3K) recruitment and activation (as demonstrated by Akt phosphorylation) either directly (ErbB4 cyt1 isoform) or indirectly (ErbB4 cyt2 isoform). We examined the ability of the four ErbB4 isoforms to induce chemotaxis and cell proliferation in response to NRG11 stimulation. Using migration assays, we observed that only ErbB4-expressing cells stimulated with NRG11 showed a significant increase in migration, whereas the growth rate remained unchanged. Additional assays showed that inhibition of PI3K (but not of phospholipase C) dramatically reduced migratory activity. Our data show that ErbB4 signaling via PI3K activation plays a fundamental role in controlling NRG11-induced migration.

Received for publication, July 23, 2004 , and in revised form, August 24, 2004.

^* This work was supported by a grant from the Compagnia di S. Paolo, (Grant MIUR-PRIN 2001), and PRONEURO (Grant FIRB RBNE01WY7P). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY375306, AY375307, and AY375308.

^¶ Both authors contributed equally to this work.

To whom correspondence should be addressed: Dipt. di Biologia Animale e dell'Uomo, Università degli Studi di Torino, Via Accademia Albertina 13, 10123 Torino, Italia. Tel.: 39-11-670-4688; Fax: 39-11-670-4692; E-mail: giovanna.gambarotta{at}unito.it.

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