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ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor

Abstract

The ERBB receptors have a crucial role in morphogenesis and oncogenesis. We have identified a new PDZ protein we named ERBIN (ERBB2 interacting protein) that acts as an adaptor for the receptor ERBB2/HER2 in epithelia. ERBIN contains 16 leucine-rich repeats (LRRs) in its amino terminus and a PDZ (PSD-95/DLG/ZO-1) domain at its carboxy terminus, and belongs to a new PDZ protein family. The PDZ domain directly and specifically interacts with ERBB2/HER2. ERBIN and ERBB2/HER2 colocalize to the lateral membrane of human intestinal epithelial cells. The ERBIN-binding site in ERBB2/HER2 has a critical role in restricting this receptor to the basolateral membrane of epithelial cells, as mutation of the ERBIN-binding site leads to the mislocalization of the receptor in these cells. We suggest that ERBIN acts in the localization and signalling of ERBB2/HER2 in epithelia.

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Figure 1: The cloning of erbin, a gene encoding a PDZ domain protein that interacts with the receptor ERBB2.
Figure 2: Characterization of ERBIN, a member of a new PDZ family.
Figure 3: ERBIN interacts preferentially with the non-activated HER1/2 receptor.
Figure 4: Basolateral localization of ERBIN and ERBB2 in human colon.
Figure 5: Figure 5 Basolateral localization of ERBIN and ERBB2 in Caco-2 cells.
Figure 6: Basolateral localization of ERBB2 in epithelial cells relies on the presence of an intact ERBIN-binding site.

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Acknowledgements

We are grateful to M. Labouesse for sharing unpublished information. We thank G. Dressler for the mouse embryonic kidney cDNA library and the pc86 and pc97 vectors, G. Alcaraz for the rat brain cDNA library, M. Sheng for the constructs expressing the Myc-tagged PSD-95 and SAP97 proteins, Y. Kohara for the C.elegans ESTs (yk294 g5, yk524 b7, yk126 a10), W-Z. Wei for the pCMV–ERBB2 construct and J. Camonis for reagents enabling us to test the interaction between Ras and ERBIN. This project is supported by INSERM, ARC and Institut Paoli-Calmettes (V.O.). H.S. is a recipient of a Japanese-French fellowship. B.M. is an Investigator of the Howard Hughes Medical Institute.

Correspondence and requests for materials should be addressed to J-P.B. The accession numbers for the mouse and human ERBIN sequences deposited in GenBank are AF263743 and AF263744, respectively.

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Borg, JP., Marchetto, S., Le Bivic, A. et al. ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor. Nat Cell Biol 2, 407–414 (2000). https://doi.org/10.1038/35017038

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