Abstract
Grb2-associated binder (Gab) docking proteins regulate signals downstream of a variety of growth factors and receptor tyrosine kinases. Neuregulin-1 (NRG-1), a member of epidermal growth factor family, plays a critical role for cardiomyocyte proliferation and prevention of heart failure via ErbB receptors. We previously reported that Gab1 and Gab2 in the myocardium are essential for maintenance of myocardial function in the postnatal heart via transmission of NRG-1/ErbB-signaling through analysis of Gab1/Gab2 cardiomyocyte-specific double knockout mice. In that study, we also found that there is an unknown high-molecular weight (high-MW) Gab1 isoform (120 kDa) expressed exclusively in the heart, in addition to the ubiquitously expressed low-MW (100 kDa) Gab1. However, the high-MW Gab1 has been molecularly ill-defined to date. Here, we identified the high-MW Gab1 as a striated muscle-specific isoform. The high-MW Gab1 has an extra exon encoding 27 amino acid residues between the already-known 3rd and 4th exons of the ubiquitously expressed low-MW Gab1. Expression analysis by RT-PCR and immunostaining with the antibody specific for the high-MW Gab1 demonstrate that the high-MW Gab1 isoform is exclusively expressed in striated muscle including heart and skeletal muscle. The ratio of high-MW Gab1/ total Gab1 mRNAs increased along with heart development. The high-MW Gab1 isoform in heart underwent tyrosine-phosphorylation exclusively after intravenous administration of NRG-1, among several growth factors. Adenovirus-mediated overexpression of the high-MW Gab1 induces more sustained activation of AKT after stimulation with NRG-1 in cardiomyocytes compared with that of β-galactosidase. On the contrary, siRNA-mediated knockdown of the high-MW Gab1 significantly attenuated AKT activation after stimulation with NRG-1 in cardiomyocytes. Taken together, these findings suggest that the striated muscle-specific high-MW isoform of Gab1 has a crucial role for NRG-1/ErbB signaling in cardiomyocytes.
Highlights
Neuregulin-1 (NRG-1), a member of the epidermal growth factor (EGF) family, serves as a paracrine factor that is shed from the endocardial and capillary endothelial cell in the heart, and exerts various effects via the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases (ErbB2, ErbB3, and ErbB4) [1,2,3]
The Roles of Striated Muscle-Specific Gab1 Isoform in Neuregulin-1/ErbB Signaling muscle-specific high-MW isoform of Gab1 has a crucial role for NRG-1/ErbB signaling in cardiomyocytes
We identified a novel high-MW Gab1 which is exclusively expressed in striated muscle, and characterized it as a crucial signaling component for the activation of PI3-kinase/AKT signaling axis downstream of NRG-1/ErbB signaling in cardiomyocytes
Summary
Neuregulin-1 (NRG-1), a member of the epidermal growth factor (EGF) family, serves as a paracrine factor that is shed from the endocardial and capillary endothelial cell in the heart, and exerts various effects via the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases (ErbB2, ErbB3, and ErbB4) [1,2,3] Among these ErbB receptors, NRG-1 activates the ErbB4 homodimer or ErbB2/ErbB4 heterodimer expressed on cardiomyocytes, and plays critical roles in both heart development and cardiac homeostasis [1,2,3,4,5]. We identified a novel high-MW Gab which is exclusively expressed in striated muscle, and characterized it as a crucial signaling component for the activation of PI3-kinase/AKT signaling axis downstream of NRG-1/ErbB signaling in cardiomyocytes
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