The Research Of The Function Of Erbin In Meditating Interaction Of Her2-β2-AR And Regulating The MAPK Signaling Pathway

Objective:Erbin(ErbB2 interacting protein)is a recently identified Her2 interacting protein by using yeast two hybrid method in 2000. It is a family member of LAP protein. Erbin contains 16 leucine-rich repeats (LRRs) in its amino terminus and a PDZ domain at its carboxy terminus. The PDZ domain of Erbin directly and specifically interacts with ERBB2/HER2. Erbin and HER2 colocalize to the lateral membrane of human intestinal epithelial cells. Erbin expresses highly in the brain and myocardium. Erbin locates at the basolateral membrane or associated with lateral junctions in polarized epithelial cells. It participates in the formation of the polarity of cells and sustains the stability of the internal environment of epithelial cells. It also participates in basolateral targeting of Her2 and other molecules. Recently, it is found that Erbin plays an important role in regulating different signaling pathways. However, its functions are largely unclear.β2 adrenergic receptor (β2-AR) belongs to the G protein coupled receptor (GPCR) family. It plays an important role in regulating the functions of cardiac muscle cells. Catecholamine regulates the functions of certain human organs to effectively cope with external stimulates.However,the constant stimulation of catecholamine can lead to the activation of GPCRs and induce the damage of cardiac muscle cells. The latest research showed that catecholamine can also activate the survival pathway of cardiac muscle cells by inducing the MARK signaling pathway. But its accurate molecular mechanism is unknown.Proto-oncogene ErbB2/Her2, a member of epidermal growth factor receptor (EGFR) family has a special spatial structure. It possesses a high ligand-independent activity. Her2 exerts many effects on the growth and differentiation of cells. Its deficiency in cardiac muscle cells leads to the dilatation of the myocardium. Our previous studies showed that Erbin mediated interaction of Her2 andβ2-AR. We also found that knock-down the expression of Erbin influenced MARK signaling induced by catecholamine.This study focuses on elucidation of interaction of Erbin-Her2-β2-AR, identification of the functional domain of Erbin involved in the interactions, and characterization of the role of Erbin in catecholamine-induced MAPK signaling activation to provide new clues for revealing pathogenesis of cardiovascular diseases.Methods:1 Co-immunoprecipitation was used to testify the interaction of Erbin, Her2 andβ2-AR.2 The different Erbin mutants were utilized to identify the functional domain that mediates the interaction between Her2 andβ2-AR using co-immunoprecipitation and confocal microscopy.3 The role of Erbin in catecholamine-induced MAPK signaling activation was testified by utilizing Erbin mutants, silencing of Erbin expression andβ2-AR agonist.Results:1 The interaction of Erbin, Her2 andβ2-AR is confirmed.2 The PDZ domain of Erbin mediates the interaction between Her2 andβ2-AR.3 Erbin plays a positive role in catecholamine-induced MAPK signaling activation.Conclusion:Erbin mediates the interaction betweenβ2-AR and Her2 via its PDZ domain; Erbin negatively regulates EGF-induced MAPK signaling pathway; Erbin plays a positive role in the activation of MARK signaling pathway induced by catecholamine.