title: Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2.
abstract: The four receptor tyrosine kinases of the ErbB family play essential roles in several physiological processes and have also been implicated in tumor generation and/or progression. Activation of ErbB1/EGFR is mainly triggered by epidermal growth factor (EGF) and other related ligands, while activation of ErbB2, ErbB3, and ErbB4 receptors occurs by binding to another set of EGF-like ligands termed neuregulins (NRGs). Here we show that the Erk5 mitogen-activated protein kinase (MAPK) pathway participates in NRG signal transduction. In MCF7 cells, NRG activated Erk5 in a time- and dose-dependent fashion. The action of NRG on Erk5 was dependent on the kinase activity of ErbB receptors but was independent of Ras. Expression in MCF7 cells of a dominant negative form of Erk5 resulted in a significant decrease in NRG-induced proliferation of MCF7 cells. Analysis of Erk5 in several human tumor cell lines indicated that a constitutively active form of this kinase was present in the BT474 and SKBR3 cell lines, which also expressed activated forms of ErbB2, ErbB3, and ErbB4. Treatments aimed at decreasing the activity of these receptors caused Erk5 inactivation, indicating that the active form of Erk5 present in BT474 and SKBR3 cells was due to a persistent positive stimulus originating at the ErbB receptors. In BT474 cells expression of the dominant negative form of Erk5 resulted in reduced proliferation, indicating that in these cells Erk5 was also involved in the control of proliferation. Taken together, these results suggest that Erk5 may play a role in the regulation of cell proliferation by NRG receptors and indicate that constitutively active NRG receptors may induce proliferative responses in cancer cells through this MAPK pathway.
authors.affiliation: Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: Esparís-Ogando
authors.forename: Elena
authors.initials: E
authors.lastname: Díaz-Rodríguez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.forename: Laura
authors.initials: L
authors.lastname: Yuste
authors.forename: Piero
authors.initials: P
authors.lastname: Crespo
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms; D002070:Butadienes / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008856:Microscopy, Fluorescence; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020880:Neuregulins / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D010797:Phthalimides / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D020880:Neuregulins; D009570:Nitriles; D010797:Phthalimides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C117146:4,5-bis(4-fluoroanilino)phthalimide; C113580:U 0126