KANK1 inhibits the tumor suppressor Scribble by competing for NOS1AP binding

KANK1 belongs to the KANK family of scaffolding proteins that is expressed in epithelial cells and connects focal adhesions with the adjacent cortical microtubule stabilizing complex. Although KANK1 overexpression studies was shown to suppress the growth of different cancer cell lines in vitro, The Cancer Genome Atlas (TCGA) database indicates that high rather than low KANK1 levels are associated with poor prognosis in a wide spectrum of human malignancies. In the present study, we addressed this discrepancy and characterized how KANK1 regulates tumor development in the Polyoma Middle T (PyMT)-driven murine breast cancer model and upon orthotopic implantation of human breast cancer cells in immune-deficient mice. Our results revealed that KANK1 promotes cell proliferation and cell survival of PyMT-transformed tumor cells in vivo. Mechanistically, KANK1 localizes to the basal side of basement membrane (BM)-attached transformed luminal epithelial cells. However, when these cells detach from the BM and disassemble integrin adhesions, KANK1 translocates to cell-cell junctions where it competes with the polarity and tumor suppressor protein SCRIB for NOS1AP binding and thereby curbs the ability of SCRIB to activate the Hippo pathway. The consequences are stabilization and nuclear accumulation of TAZ, growth and survival of tumor cells and elevated breast cancer development. Importantly, the oncogenic pathway induced by KANK1 at cell-cell junctions also operates in human breast cancer.