Abstract 617: ErbB2 Receptor Tyrosine Kinase Interacts with the Dystrophin Associated Protein Complex in Transverse Tubules of a Dilated Cardiomyopathy Model
Background: Dystrophin (Dys) associates with a protein complex (DAPC) which includes: an extracellular protein α-dystroglycan; the transmembrane glycoproteins, β-dystroglycan (βDG) and α, β, γ, δ-sarcoglycans (SG) and the structural component of caveolae, caveolin-3 (Cav3). Dys and Cav3 compete for binding to βDG via their WW domains. δSG deficiency manifests as Limb Girdle Muscular Dystrophy (LGMD2F), with dilated cardiomyopathy (DCM) occurring in patients. We verified DCM in the δSG deficient (TO2) hamster at 15 wks by systolic dysfunction and wall thinning. Cav-3, DAPC and the receptor tyrosine kinase, ErbB2 are localized to myocardial T-tubules. DCM occurs in ErbB2 knock out models. Src associates with ErbB2. We examined the hypothesis that the association of ErbB2 with DAPC and Src determines the transition from normal myocardium to DCM. This is the first report of T-tubular co-localization of ErbB2 with DAPC and Src in a DCM model.
Methods and Results: The T-tubular co-localization of ErbB2 and: βDG, Dys or Cav3; was determined by confocal microscopy. T-tubular ErbB2 co-localized with Cav3 in the F1B group. No ErbB2-Cav3 co-localization was observed in the TO2 DCM group. ErbB2 co-localized with Dys in the TO2 DCM group. No ErbB2-Dys co-localization was observed in the F1B group. T-tubular co-localization of ErbB2 and βDG was observed in the F1B group. Co-immunoprecipitation studies demonstrated:
An association of ErbB2 and βDG in the F1B group and not in the TO2 DCM group and
An association of ErbB2 with Src in the TO2 group that is decreased in the F1B group.
Conclusions: This is the first report that correlates the loss of ErbB2-Cav3-βDG association and the onset of ErbB2-Src-Dys association with the induction of DCM in the TO2 model. This suggests the novel hypothesis that ErbB2 is transferred from a Cav3-βDG-DAPC complex in the F1B group to a Src-Dys-DAPC complex in the TO2 DCM model. We propose that the association of ErbB2 with a Cav3-βDG complex induces tyrosine kinase activity. In contrast the association of ErbB2 with a Src-Dys-DAPC complex inhibits ErbB2 tyrosine kinase activity, initiating the onset of DCM. The ErbB2-Src-Dys-DAPC complex presumably induces the patho-physiologic correlate of the DCM that is observed in the ErbB2 knock-out model.