Disease relevance of ERBB2IP

• Nonetheless, one cannot yet exclude that ERBB2IP is a candidate for human blistering disorders such as epidermolysis bullosa [1].
• Disruption of ERBB2IP is not associated with dystrophic epidermolysis bullosa in both father and son carrying a balanced 5;13 translocation [1].
• We used a C-terminally displayed phage peptide library to identify optimal ligands for the Erbin PDZ domain [2].
• In addition, a change in the dynamics of the Erbin/Nod2 complex was observed during Shigella flexneri infection [3].
• Comparative analysis of the expression of ERBIN and Erb-B2 in normal human skin and cutaneous carcinomas [4].

High impact information on ERBB2IP

• ERBIN and ERBB2/HER2 colocalize to the lateral membrane of human intestinal epithelial cells [5].
• Consequently, the biological function of ZO-1 is also broadened, as it interacts with both tight and adherens junction proteins, whereas Erbin is restricted to adherens junctions [6].
• Site(-1) was found to be monospecific in the Erbin PDZ domain (accepts tryptophan only), bispecific in the first PDZ domain of ZO-1 (accepts tryptophan or tyrosine), and promiscuous in the Scribble PDZ domains [7].
• Our data further indicate that the endocytosis deficiency of ErbB2 and of EGFR-ErbB2 heterodimers/oligomers cannot be explained by anchoring of ErbB2 to PDZ-containing proteins such as Erbin [8].
• Although it interacts with the ErbB2 C terminus through the PDZ domain, Erbin has no effect on ErbB2 tyrosine phosphorylation or binding to the adaptor proteins Shc and Grb2 [9].

Chemical compound and disease context of ERBB2IP

• Alanine and homolog scanning mutagenesis (in a combinatorial phage display format) identifies Erbin side chains that make energetically important contacts with the ligand [10].

Biological context of ERBB2IP

• However, loss of function of one ERBB2IP copy or expression of a putative novel ERBB2IP fusion protein did not apparently modulate the DEB phenotype in both translocation patients [1].
• ERBIN belongs to the newly described LAP (LRR and PDZ) protein family, whose function is crucial in non vertebrates for epithelial homeostasis [11].
• BACKGROUND: ERBIN, an ErbB2 receptor-interacting protein, belongs to a recently described family of proteins termed the LAP [leucine-rich repeats and PSD-95/dLg-A/ZO-1 (PDZ) domains] family which has essential roles in establishment of cell polarity [12].
• Origins of PDZ domain ligand specificity. Structure determination and mutagenesis of the Erbin PDZ domain [10].
• Since phosphorylation of tyrosine -7 plays a critical role in ErbB2 function, the selective binding and sequestration of this residue in its unphosphorylated state by the Erbin PDZ provides a novel mechanism for regulation of the ErbB2-mediated signaling and oncogenicity [13].

Anatomical context of ERBB2IP

• Erbin is concentrated in postsynaptic membranes at the neuromuscular junction and in the central nervous system, where ErbB2 is concentrated [14].
• Erbin binds to p0071 in vitro and in vivo in a PDZ domain-dependent manner, and both proteins colocalized in desmosomes of epithelial cells [15].
• Furthermore, we provide evidence that Erbin interacts with PSD-95 in both transfected cells and synaptosomes [14].
• We show here that Erbin interacts with p0071 (also called plakophilin-4), an armadillo repeat protein linked to the cytoskeleton [15].
• CONCLUSION: These results show that ERBIN interacts in vivo with p0071 and that it may be involved in the organization of adherens junctions and the desmosomes of epithelia [12].

Associations of ERBB2IP with chemical compounds

• Expression of Erbin increases the amount of ErbB2 labeled by biotin in transfected cells, suggesting that Erbin is able to increase ErbB2 surface expression [14].
• Erbin contains a class I PDZ domain that binds to the C-terminal region of the receptor tyrosine kinase ErbB2, a class II ligand [13].
• The isopropyl group of valine at position -2 of the ErbB2 peptide interacts with the Erbin Val(1351) and displaces the peptide backbone away from the alpha-helix, elucidating the molecular basis of class II ligand recognition by a class I PDZ domain [13].
• Phosphorylation of tyrosine -7 abolishes this interaction but does not affect the binding of the four C-terminal peptidic residues to PDZ, as revealed by the crystal structure of the Erbin PDZ complexed with a phosphotyrosine-containing ErbB2 peptide [13].
• The binding partners of Erbin, BP230 (BPAG1) and the integrin beta4 subunit, both involved in hemidesmosome (HD) function, and the presence of Erbin in HD suggested that it plays a role in establishment and maintenance of cell-basement membrane adhesions [1].

Physical interactions of ERBB2IP

• We previously described Erbin as a mammalian LET-413 homologue interacting with ERBB2/HER2, an epidermal growth factor receptor family member [15].
• Endogenous ERBIN was co-immunoprecipitated with p0071 [12].
• Mutagenesis and peptide competition experiments showed that the association of Erbin with the cadherin-catenin complex was mediated by the interaction of its PDZ domain with the C-terminal PDZ domain-binding motifs (DSWV-COOH) of ARVCF and delta-catenin [2].
• The Erbin PDZ domain binds with high affinity and specificity to the carboxyl termini of delta-catenin and ARVCF [2].
• A second pool of Lano is complexed to Erbin [16].

Co-localisations of ERBB2IP

• At these cell-cell contact regions, ERBIN co-localizes with p0071 [12].
• Furthermore, ERBIN and ErbB2 were colocalized with PAPIN on the lateral membrane [17].

Other interactions of ERBB2IP

• ERBIN associates with p0071, an armadillo protein, at cell-cell junctions of epithelial cells [12].
• Erbin and ERBB2/HER2 are located in the basolateral membranes of epithelial cells [15].
• These results suggest that delta-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex [2].
• Finally, we showed that endogenous delta-catenin and Erbin co-localized in and co-immunoprecipitated from neurons [2].
• Role for erbin in bacterial activation of Nod2 [3].

Analytical, diagnostic and therapeutic context of ERBB2IP

• Immunofluorescence microscopy with a newly generated anti-Nod2 monoclonal antibody showed that Erbin and Nod2 partially colocalize in human cells [3].
• In order to identify proteins that bind to the PDZ domain of Erbin, we tested the C-termini of several proteins in a yeast two-hybrid assay [18].
• Chromatin immunoprecipitation assays show that the LAP2 promoter is bound by endogenous E2F in vivo [19].

References