Upstream Regulation of the Hippo Size Control Pathway

The newly discovered Salvador-Warts-Hippo (SWH) pathway is a key regulator of tissue growth during both development and disease. The first identified components of this pathway represent core downstream effector proteins: the kinases Warts and Hippo; the adaptor proteins Salvador and Mats; and the transcriptional coactivator Yorkie. More recently, a surprising number of proteins have been implicated as upstream regulators of the SWH pathway, including: the planar cell polarity cadherins Fat and Dachsous; the FERM-domain proteins Expanded and Merlin; the WW-domain protein Kibra; the Ras-association family protein dRASSF; and the apicobasal polarity proteins lethal giant larvae, atypical protein kinase C and Crumbs. The identification of a large cohort of upstream regulatory proteins suggests that core SWH pathway proteins are poised to respond to diverse stimuli that must be integrated in a coordinated fashion. Here, we review the existing knowledge of upstream SWH pathway proteins and discuss possible mechanisms of action and signal integration.