Hippo Pathway and Apoptosis

The Hippo pathway is an established pathway that regulates apoptosis. The earliest characterisations of the mammalian MST1/2 kinases indicated that they were potent inducers of apoptosis in response to a wide range of stimuli. Elucidation of pathway components via genetic screens in Drosophila revealed that signalling through the Hippo pathway is required for the induction of apoptosis during development. Central to control of developmental apoptosis in Drosophila is the regulation of the transcriptional co-activator Yki, whose interaction with transcription factors including Sd, Mad and Tsh/Hth drives the transcription of potent apoptotic inhibitors including Diap-1 and the microRNA Bantam. In mammals it is clear that the core MST1/2-LATS1/2 kinase cassette has various downstream components which lead to apoptosis including the transcription of pro-apoptotic target genes via multiple transcription factors, caspase activation and histone modification. The LATS1/2 kinases and Yap function in a complex network with p53 and its associated regulatory proteins from the ASPP family which, through association with Yap, can have opposing effects on apoptosis. While it is clear that Yap is an important inhibitor of apoptosis in mammals and is subject to similar regulation to that of Yki, Yap also promotes the transcription of pro-apoptotic target genes via association with p73. Evidence suggests that the tumour suppressor RASSF1A is an important determinant in mediating Yap pro-apoptotic activities through regulation of Yap transcription factor interactions.