Role and regulation of human tumor suppressor SUFU in Hedgehog signaling

Originally identified as factors affecting Drosophila embryogenesis, the Hedgehog (Hh) pathway is one of the primary signaling systems that specify patterns of cell growth and differentiation during vertebrate development. Mutations in various components of this pathway frequently occur in tumors originated from the skin, cerebellum, and skeletal muscle, and abnormal pathway activity is associated with a subset of lung, digestive tract, pancreatic, and prostate cancers. Because of these potent biological activities, this pathway is negatively regulated at multiple levels to ensure appropriate signaling responses. Suppressor of fused (Sufu) is one such negative regulator of Hh signaling. Although not essential in Drosophila, Sufu is absolutely required for mouse embryonic development. Mutations of Sufu are associated with a childhood brain tumor in human and an increased susceptibility to the same type of cancer in the TP53 null background in mice, and RNAi-mediated silencing of Sufu is sufficient to activate the Hh signaling in cultured fibroblasts. All these data point to a central role of Sufu in controlling the vertebrate Hh signaling pathway; however, for years what exactly Sufu does in the Hh pathway and what controls its activity remains a deep mystery. This chapter will go over all studies curated in the PubMed database with Sufu as a main subject during the past 17 years, and attempt to provide a balanced view on Sufu gene and protein structure, activities in Drosophila as well as mammalian development, and its involvement in cancer.