Fig. 8

Overview of CSMD1 proposed mechanism of action. (1) CSMD1 strongly interacted with either monomeric or dimeric EGFR both in the extra- and intracellular domains. This interaction led to (2) diminished EGFR dimers formation and (3) EGFR signaling (decreased EGFR intracellular kinase domain phosphorylation and PI3K-AKT signaling cascade activation). (4) In the presence of CSMD1, EGFR was highly ubiquitinylated, thus exhibited altered endosomal trafficking. (5) CSMD1 enhanced EGFR degradation, while EGFR was faster localized to early (EEA1) and late (LAMP1) endosomes. (6) CSMD1-expressing BBCs were more sensitive upon chemotherapy treatment, demonstrating lower drug efflux activity and increased levels of cleaved caspase-3