PURPOSE: Anti-p185HER2/neu monoclonal antibody (mAb) that can induce phenotypic reversion and monoclonal antibodies specific for the p185HER2/neu growth factor receptor that are able to diminish its kinase-signaling properties represent a specific advance in the therapy for p185HER2/neu-expressing human cancers. With mAb treatment, down-regulation of p185HER2/neu surface receptors and attenuation of the kinase-signaling properties have been observed and regarded as a basic phenomenon; however, the mechanisms for mAb-induced phenotypic reversion are not clear. METHODS: We used human tumor-cell lines of SK-BR-3, T6-17, and U373MG. With immunoprecipitation and Western blotting, we investigated the changes in p185HER2/neu receptor phosphorylation and the expression of signal-regulatory proteins (SIRPs) after mAb treatment. To identify the proteins interacting with Tat-binding protein-1 (TBP1), we used the Clonotech Gal4 matchmaker two-hybrid system. RESULTS: Minimal to moderate reduction in phosphotyrosine (pTyr) content was observed in SK-BR-3 and T6-17 cells with short-term (10-30 minutes) incubation after mAb treatment, but that did not alter total p185HER2/neu receptor density. SIRPs phosphorylation after peptide treatment was increased. With mAb treatment, three proteins were shown to interact with TBP1, and all of the interacting proteins are subunits of proteasome 26S. Collectively, anti- p185HER2/neu mAb or peptide down-regulates the surface receptors and attenuates the kinase signaling, which then both induces higher proteasome activity through increased TBP1 and increases SIRPs expres sion. CONCLUSION: Increased proteasomal activity may degrade abnormal proteins and increased SIRPs may regulate signal transduction toward the norm. Therefore, activation of a protein-degradation pathway and induction of signal-regulatory proteins may be possible mechanisms for the ultimate anti-tumor effects of the anti-p185HER2/neu mAb or peptide.