Abstract 137: Gab Family Scaffolding Adaptor Proteins are Essential for Postnatal Maintenance of Cardiac Function via Neuregulin-1/ErbB Signaling
Backgrounds: Grb2-associated binder (Gab) family proteins belong to scaffolding adaptor proteins and undergo tyrosine-phosphorylation after stimulation with various growth factors and cytokines. Tyrosine-phosphorylated Gab family proteins associate with tyrosine phosphatase SHP2 and p85 phosphatidylinositol-3 kinase subunit, leading to activation of extracellular signal-regulated kinase (ERK) and AKT, respectively. Among Gab family proteins, mRNAs of Gab1 and Gab2 were detected in the murine heart by RT-PCR. Since Gab1 and Gab2 are capable of complementing each other in some signaling pathways, we tried to elucidate the role of Gab family proteins in the myocardium by creating cardiomyocyte-specific Gab1/Gab2-double knockout (DKO) mice.
Methods & Results: DKO mice were generated by crossing cardiomyocyte-specific Gab1-knockout mice with conventional Gab2-knockout mice. Although DKO mice were viable, they exhibited marked ventricular dilatation and deteriorated contractility with aging. Approximately 70% of DKO mice died of heart failure between 3 and 72 weeks. Among various growth factors, neuregulin-1β (NRG-1β), a paracrine factor shed from endocardial and microvascular endothelium in the heart, most strongly induced tyrosine-phosphorylation of both Gab1 and Gab2 and subsequent association of Gab1/Gab2 with SHP2 and p85. NRG-1β induced activation of ERK and AKT in the hearts of control mice, but not in those of DKO mice. Intriguingly, endocardial fibroelatsosis and abnormally dilated vessels were observed exclusively in the ventricles of DKO mice, suggesting the endothelial dysfunction in the heart. To explore the molecular target of NRG-1β/ErbB/Gab1/Gab2-signaling pathway in the myocardium, we performed DNA microarray analysis and found that administration of NRG-1β upregulated expression of an endothelium-stabilizing factor, angiopoeitin-1, in the myocardium of control mice, but not in those of DKO mice, which presumably accounted for the pathological abnormalities in the DKO mice hearts.
Conclusion: In the NRG-1β/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary/endocardial endothelium in the postnatal heart.