Molecular mechanisms for antibody-induced endocytosis of ErbB2

The four receptor tyrosine kinases of the ErbB family mediate the activation of a complex network of signalling pathways that regulate cell proliferation, differentiation, and survival. Because of their central role in the regulation of these cellular processes, the receptors are often found to have abnormal activity in cancer cells. This makes them important targets for cancer treatment. The ErbB proteins depend on dimerization to exert their function and they are generally downregulated through the internalization and degradation of activated receptors. ErbB2, however, is special in that it is resistant to internalization and inhibits internalization of other ErbBs upon heterodimerization. For this reason, therapeutic antibodies have been developed that block the receptors ability to dimerize and/or induces their downregulation. In the present study, two new therapeutic antibodies against ErbB2 are investigated. The study shows that they induce internalization and degradation of the receptor. Investigations into which endocytic pathway the cells use to internalize ErbB2 upon treatment with these antibodies reveal that the main pathway(s) used is/are most likely dynamin-dependent. Further, the study shows that the antibodies induce both phosphorylation and ubiquitination of the receptor. The activities of the new antibodies were also compared to those of the therapeutic antibodies trastuzumab and pertuzumab, which are already in clinical use, and the new antibodies appear to be more effective at inducing downregulation of ErbB2