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.Receptor tyrosine kinases of the ErbB family play essential roles in several physiological processes, such as cell growth (11,36,66), differentiation, and tissue development (8,55,61), and have been implicated in pathological processes, such as tumor generation and/or progression (36,66). This family comprises four structurally related transmembrane receptors, the epidermal growth factor (EGF) receptor (EGFR or ErbB1/HER1), ErbB2 (neu/HER2), ErbB3 (HER3), and ErbB4 (HER4) (36,66). Activation of ErbB receptors may occur by ligand binding (67,68) or by overexpression of the receptor (36, 57), the latter mechanism being particularly relevant in certain pathologic instances such as cancer (30,(62)(63)(64). Ligand-mediated activation of ErbB receptors occurs by interaction of the ectodomain of these receptors with specific members of the EGF family of ligands (11,48). This family includes EGF, transforming growth factor ␣, amphiregulin, betacellulin, and epiregulin, which preferentially bind to and activate the EGFR (3,48,65). A second group of EGF-like ligands, the neuregulins (NRGs), bind to ErbB3 and ErbB4 (6,38,53). Ligand-induced activation of ErbB receptors is complex and often includes oligomeric interactions between different ErbB receptors (19,54). Thus, upon ligand binding, ErbB recepto...

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