The polyomavirus middle T-antigen oncogene activates the Hippo pathway tumor suppressor Lats in a Src-dependent manner

Abstract

The polyomavirus middle T antigen (PyMT) is an oncogene that activates the non-receptor tyrosine kinase, c-Src, and physically interacts with Taz (WWTR1). Taz is a pro-oncogenic transcription coactivator of the Tead transcription factors. The Hippo tumor suppressor pathway activates the kinase Lats, which phosphorylates Taz, leading to its nuclear exclusion and blunting Tead coactivation. 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 in the presence of PyMT, wild-type Taz was phosphorylated by Lats, in a Src-dependent manner. Consistently, a Lats refractory Taz mutant did not undergo cytoplasmic retention by PyMT. We show that Yap, the Taz paralog, and Shp2 phosphatase were nuclear excluded as well. Our findings describe a noncanonical activation of Lats, and an unprecedented Tead-independent role for Taz and Yap in viral-mediated oncogenesis.

αE-catenin inhibits a Src–YAP1 oncogenic module that couples tyrosine kinases and the effector of Hippo signaling pathway

“…This pathway is activated in confluent cells, where it suppresses YAP1 nuclear localization and thereby inhibits its transcriptional activity (Zhao et al 2007). It had been demonstrated previously that SRC and other SFKs can positively (Shanzer et al 2015) and negatively regulate canonical Hippo signaling pathway (Enomoto and Igaki 2013;Pijuan-Galito et al 2014;Kim and Gumbiner 2015;Kwon et al 2015). In accordance with these findings, we observed negative regulation of S127 YAP1 phosphorylation in sparse keratinocytes (Supplemental Fig.…”

Biphasic Regulation of Yes-associated Protein (YAP) Cellular Localization, Phosphorylation, and Activity by G Protein-coupled Receptor Agonists in Intestinal Epithelial Cells

“…Several studies indicate that YAP acts as a context-specific oncogene (11) and that the Hippo pathway inhibits its activity. Despite intense interest in this novel pathway, many important questions relating to its function remain unanswered as follows: 1) the mechanism(s) by which upstream signals feed into the Hippo cascade remain incompletely defined; 2) YAP not only acts as a transcriptional co-activator in the nucleus but also mediates biological functions in other cellular locations, including the cytoplasm (12,13); and 3) YAP crosstalks with other important signaling pathways, but the biologi-cal outcome (positive or negative) of these interactions remains unclear and is likely cell context-dependent. Even at the most fundamental level, the precise role of YAP in intestinal epithelial cell proliferation remains incompletely understood, as evidence for both growth-stimulatory and growth-suppressive roles of YAP/TAZ has been presented (14 -17).…”

Transformation by Polyomavirus Middle T Antigen Involves a Unique Bimodal Interaction with the Hippo Effector YAP

“…TAZ, a YAP family member with structural similarities to YAP, is another effector of the Hippo pathway. There is evidence that TAZ is also important in MT transformation (63). Figure 2B also shows a comparison of YAP and TAZ knockdowns.…”

“…The sequence identity between ST and the N terminus of MT, together with the knowledge that MT binds the YAP relative TAZ (62,63), led us to hypothesize that MT may interact with YAP. Here data from mass spectrometry (MS) and coimmunoprecipitation experiments demonstrate that YAP is indeed a novel MT interactor.…”