Src Inhibits The Hippo Pathway Through Tyrosine Phosphorylation Of Lats1

The Hippo pathway was initially identified in Drosophila by genetic mosaic screens for tumor suppressor genes.Components of the Hippo pathway are highly conserved in mammals.In the Hippo pathway,Mstl/2 kinases together with the adaptor protein Savl phosphorylate Latsl/2 kinases.Interaction with an adaptor protein Mob is also important for Latsl/2 activation.Activated Latsl/2 in turn phosphorylate and inhibit Yes-associated protein(YAP).YAP is a key downstream effector of the Hippo pathway,and is a transcriptional co-activator that mainly interacts with TEAD family transcription factors to promote gene expression.The Hippo pathway responds to upstream signals such as mechanical stress,cell polarity complexes,cytoskeleton remodeling and GPCR signals.The Hippo pathway regulates cell proliferation,apoptosis and stem cell self-renewal,thus plays a key role in limiting organ size.Hippo pathway inactivation causes dramatic organ enlargement followed by tumorigenesis in animal models.Importantly,while Hippo pathway deregulation has been found in many human cancers,the underlying mechanisms remain largely obscure.In this study we found that tyrosine phosphorylation of Latsl is a mechanism underlying Latsl regulation by cell adhesion.Through a tyrosine kinase library screen,we identified Src as the kinase directly phosphorylates Latsl on multiple residues causing attenuated Mob binding and structural alteration of the substrate-binding pocket in the kinase domain.Cell-matrix adhesion activates the Hippo pathway effector Yes-associated protein(YAP)partially through Src-mediated phosphorylation and inhibition of Latsl.Furthermore,we show that aberrant Src activation abolishes the tumor suppressive activity of Lats1 and induces tumorigenesis in a YAP-dependent manner.Importantly,the protein levels of Src in human breast cancer tissues correlate with the accumulation of active YAP dephosphorylated on the Latsl target site.These findings reveal tyrosine phosphorylation of Latsl by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis.