The
polyomavirus middle T antigen (PyMT) is an oncogene which activates the
non-receptor tyrosine kinase, c-Src, and physically interacts with Taz. Taz is
a pro-oncogenic transcription co-activator of the Tead transcription factors. The
Hippo tumor suppressor pathway activates the Lats kinase, which phosphorylates
Taz, leading to its nuclear exclusion and functionally neutralizing it in
supporting Tead co-activation. We found
that Taz was required for transformation by PyMT, but counter intuitively, Taz
was exclusively cytoplasmic in the presence of PyMT. We demonstrate that PyMT induced
Taz phosphorylation by Lats in a Src-dependent manner. Furthermore, Taz mutants
that escaped Lats phosphorylation were refractory to PyMT-induced cytoplasmic retention.
Yap, the Taz paralog, was similarly regulated by PyMT. Our study demonstrates activation of the Hippo
tumor suppressor pathway by a viral oncogene.
Furthermore, it reveals a non-canonical, Tead-independent role for Taz
in transformation.
