title: β2-AR-induced Her2 transactivation mediated by Erbin confers protection from apoptosis in cardiomyocytes.
abstract: BACKGROUND
  Her2 and β2-adrenergic receptor (β2-AR) can form a heterocomplex in cardiomyocytes and agonists can induce Her2 transactivation, which is important for cardiovascular homeostasis. The scaffolding molecules that mediate β2-AR/Her2 interaction are currently unknown. Erbin, a PDZ domain-containing protein is a binding partner of Her2. The C-terminus of β2-AR harbors a PDZ domain-binding motif. Hypothesis of this study is that Erbin may organize the assembly of β2-AR/Her2 complex.
  
  
  METHODS
  The interaction among β2-AR, Her2 and Erbin was investigated in COS-7, HEK-293 and H9c2 cells and rat brain and heart tissues by coimmunoprecipitation. The β2-AR binding region of Erbin was identified by utilizing the Erbin deletion mutants. The functional significance of Erbin in cardiomyocytes was determined by Erbin silencing, contraction frequency measurement and cellular apoptosis assays.
  
  
  RESULTS
  Erbin was able to form a complex with both exogenous and endogenous β2-AR and Her2 in the presence of isoproterenol (ISO). Deletion of the Erbin LRR domain did not affect its binding to β2-AR and Her2, whereas lacking of the PDZ domain lost the ability of Erbin. Silencing of Erbin greatly abrogated ISO-induced activation of ERK. The treatment of H9c2 cells transfected with the Erbin siRNA with ISO caused severe cell apoptosis. Knock-down of Erbin expression in primary neonatal rat cardiomyocytes led to a remarkable reduction of the beating frequency after ISO stimulation.
  
  
  CONCLUSIONS
  Erbin mediates catecholamine-induced β2-AR/Her2 complexation and promotes catecholamine-induced activation of ERK signaling in cardiomyocytes, conferring protection of cardiomyocytes from apoptosis induced by chronic catecholamine stimulation.
authors.affiliation: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing 100850, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhao
authors.forename: Meiru
authors.initials: M
authors.lastname: Hu
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.forename: Lu
authors.initials: L
authors.lastname: Qian
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Yang
authors.forename: Yabin
authors.initials: Y
authors.lastname: Hu
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D018343:Receptors, Adrenergic, beta-2; C517630:erbin protein, rat; C483804:Erbb2 protein, rat