ErbB2 is central to the integration of multiple signaling pathways involved in cardiac function

ErbB2 is a member of the epidermal growth factor receptor (EGFR/erbB1) family of tyrosine kinase receptors. Mutations resulting in the over-expression of erbB2 exhibit ligand-independent constitutive activation of its kinase domain that contributes to the pathogenesis of a variety of human cancers. The important role of erbB2 function in the adult heart was first observed in heart- specific erbB2 mutant mice (1, 2), which develop a phenotype consistent with that of dilated cardiomyopathy. The requirement of erbB2 in adult cardiac physiology was further demonstrated in clinical studies of breast cancer patients treated with Herceptin (Trastuzumab), a humanized monoclonal antibody targeting human erbB2 (Her2). A subset of these patients developed a similar cardiomyopathy to that observed in the heart-specific erbB2 mutant mice (3). In an effort to establish how the loss of erbB2-dependent signaling results in cardiac dysfunction, we developed a method for the isolation and culture of adult cardiac myocytes from wild type and erbB2 heart-specific mutant mice. In a combination of in vitro and in vivo studies, we show that erbB2 is required for key cardioprotective signaling pathways important for adult cardiac function. The present studies confirm the concept that the erbB receptor ligand, Neuregulin (NRG), requires erbB2 for NRG- dependent signaling by demonstrating that NRG-induced activation of the extracellular signal-regulated kinase 1/ 2 (Erk1/2) mitogen activated protein kinase (MAPK) survival pathway is absent in heart-specific erbB2 mutant mice. Interestingly, we show that erbB2 is not required for Erk1/2 activation in response to epidermal growth factor, another erbB receptor ligand. We extended our studies of the requirement of erbB2 for Erk1/2 activation elicited by other classes of ligands. We established that erbB2 is critical for G-protein coupled receptor (GPCR) agonists-, Leukemia Inhibitory Factor- (LIF), and Insulin- induced Erk1/2 activation. We established that erbB2 is required for both NRG- and LIF-induced signal transducer and activator of transcription 3 (STAT3) activation, another key cardioprotective signaling pathway. We extended our observations for the requirement of erbB2 in the cross-talk and signal integration in response to multiple classes of ligands by demonstrating that erbB2 forms a ligand-induced complex with GPCRs in vivo and in vitro and, importantly, is transactivated by a GPCR in adult mouse cardiac myocytes. We further showed that EGFR is not required for cross-talk with GPCR for GPCR agonist- induced Erk1/2 activation, as confirmed by our studies utilizing EGFR null cell lines. The ability of erbB2 to complex with multiple classes of receptors suggests a potential mechanism for erbB2 in integrating signaling network