The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1PSD-95/DLG/ZO-1 domain proteins

Identification of protein complexes associated with the ERBB2/HER2 receptor may help unravel the mechanisms of its activation and regulation in normal and pathological situations. Interactions between ERBB2/ HERS and Src homo logy 2 or phosphotyrosine binding domain signaling proteins have been exten sively studied. We have identified ERBIN and PICK1 as new binding partners for ERBB2/HER2 that associate with its carboxyl terminal sequence through a PDZ (PSD 95/ DLG/ZO-1) domain. This peptide sequence acts as a dominant re tention or targeting basolateral signal for receptors in epithelial cells. ERBIN belongs to the newly described LAP (LRR and PDZ) protein family, whos e function is crucial in non vertebrates for epithelial homeostasis. Wherea s ERBIN appears to locate ERBB2/ HERS to the basolateral epithelium, PICK1 is thought to be involved in the clustering of receptors. We show here that ERBIN and PICK1 bind to ERBB2/HER2 with different mechanisms, and we propo se that these interactions are regulated in cells. Since ERBIN and PICK1 te nd to oligomerize, further complexity of protein networks may participate i n ERBB2/HER2 functions and specificity.