The γ subunit of the major histocompatibility complex (MHC) class II complex, 
CD74, is overexpressed in a significant proportion of metastatic breast tumors, 
but the mechanistic foundation and biologic significance of this phenomenon are 
not fully understood. Here, we show that when CD74 is overexpressed in human 
cancer and noncancerous epithelial cells, it interacts and interferes with the 
function of Scribble, a product of a well-known tumor suppressor gene. 
Furthermore, using epithelial cell lines expressing CD74 under the control of 
tetracycline-inducible promoter and quantitative high-resolution mass 
spectrometry, we demonstrate that, as a result of CD74 overexpression, the 
phosphorylation pattern of the C-terminal part of Scribble undergoes specific 
changes. This is accompanied with a translocation of the protein from the sites 
of cell-to-cell contacts at the plasma membrane to the cytoplasm, which is 
likely to effectively enhance the motility and invasiveness of the cancer cells.