Mammalian Hippo kinase pathway is downregulated by BCL-2 via protein degradation.

Mammalian ste20-like kinase (MST) signaling pathway plays a significant part in control of cell death and cell cycle. It was originally found as Hippo pathway in Drosophila and composed of MST kinase and Salvador-1 (SAV1), a scaffold protein. In mammalian cells, MST pathway induces cell-cycle exit and apoptosis in response to various signals. BCL-2, an anti-apoptotic protein, inhibits cell death and plays an important part in tumorigenesis. In the present report, we present evidence showing that BCL-2 is a new regulator of MST pathway. First, protein levels of MST2 and SAV1 were reduced significantly by co-expression of BCL-2. Physical interaction of BCL-2 with SAV1 was correlated with proteasomal degradation of SAV1 and MST2 proteins. In SH-SY5Y neuroblastoma cell line expressing a high level of BCL-2 but low levels of MST2 and SAV1, siRNA-induced knockdown of BCL-2 restored the expression of MST2 and SAV1. Inhibition of BCL-2 with BAD or ABT-737, a BCL-2 inhibitor, reversed its effect on MST2 and SAV1 proteins. ABT737 increased HEK293 cell death significantly when both MST2 and SAV1 were co-expressed. These results suggest that cancer cells may avoid cell death through enhanced expression of BCL-2 which down-regulates the pro-apoptotic MST pathway.