Regulation of the Hippo pathway by the non-receptor tyrosine kinases (nRTKs); how PTMs switch oncogenic to tumor suppressive function

The Hippo pathway is an evolutionarily conserved pathway from flies to humans regulating development, organ size and cell fate. The pathway is activated by serine/threonine (S/T) kinases Mst1/2 and Lats1/2 at its core. Lats phosphorylation of the downstream effectors Yap and Taz prevents their nuclear function in promoting cell proliferation, hence Lats kinases are tumor suppressors. We and others have reported that Yap and Taz are also regulated by non-receptor tyrosine kinases (nRTK), mainly Src family kinase (SFKs) and c-Abl. The nRTK-Yap/Taz cascade plays pivotal roles in cell fate determination by overriding canonical Hippo suppressive function. Yap phosphorylation by c-Abl promotes cell death, in response to DNA damage. DNA damage activates c-Abl to phosphorylate Yap and p73 and increases their association and function in inducing the expression of pro-apoptotic genes. In contrast, the Src-Yap/Taz cascade regulates oncogenesis. During cellular transformation by the polyomavirus middle T-antigen (PyMT) oncogene, Src activates the core Hippo pathway tumor suppressor Lats to facilitate Yap/Taz cytoplasmic retention. Furthermore, PyMT-mediated Src activation inhibits Taz degradation by the SCF-beta-TrCP E3-ubiquitin ligase. These findings suggest that the post-translational modification (PTM) modes of Yap and Taz switch their function from oncogene to tumor suppressor.