Activation of the tyrosine kinase receptor ErbB4 leads to various cellular responses such as proliferation, survival, differentiation and chemotaxis. Two pairs of ErbB4 isoforms, differing in juxtamembrane (JMa/JMb) and C termini (cyt1/cyt2), have been described, the latter being characterized by the presence (cyt1) or absence (cyt2) of a cytoplasmic exon with a docking site for PI3K. Through ErbB4 stable transfection in a neural progenitor cell line endogenously expressing the other ErbB family members (ErbB1, 2, and 3), we have shown that neuregulin1ß1 (NRG1ß1) stimulus triggers ErbB4 tyrosine phosphorylation and PI3K recruitment and activation, either directly (cyt1 isoform) or indirectly (cyt2), and eventually cell migration. We hypothesized that ErbB4-cyt2/ErbB3 heterodimerization could account for PI3K recruitment. By transient transfection of COS-7 cells we demonstrated that, unlike ErbB4 cyt1, ErbB4 cyt2 needed ErbB3 to recruit PI3K. To better examine the role played by ErbB3 in ErbB4-cyt2 signal transduction, we produced a siRNA against ErbB3 to test the ability of cells missing ErbB3 to migrate in response to NRG1ß1 stimulus. Supported by MURST and Compagnia di San Paolo.
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