DREF, a Concertmaster for Hippo Pathway and JNK Pathway in Drosophila

Coordination of positive and negative regulation for cell proliferation is essential to achieve organ formation with proper size. During normal development and regeneration of organs such as after surgical excision, the organs reach at each proper size with cell proliferation and its arrest at proper timing. Studies, in the past decade, have defined a kinase cascade as a key signal transduction pathway to interpret this mechanism. The Hippo pathway was firstly identified in Drosophila as a tumor-suppressive signal cascade and plays a crucial role in controlling organ size [1-7]. Interestingly, its core kinases cassette is conserved evolutionally among metazoans, consisting of four proteins, Hippo (Hpo), Salvador (Sav), Mob (Mats) and Warts (Wts) in Drosophila [1-10] (Figure 1), and MST1/2, WW45, Mob1/2 and Lats1/2 in mammals, respectively [11-17]. The Ste20-like kinase, Hpo is activated by phosphorylation [18], then the activated Hpo phosphorylates Wts, Sav, and Mats [7,19]. Sav binds to both Hpo and Wts to facilitate its reaction by serving as a scaffold [7]. Mats functions as a co-factor of Wts [10]. Then the activated Wts phosphorylates and inactivates the transcriptional co-activator Yorkie (Yki) [20]. Consequently, the inactivated Yki is retained in cytoplasm, resulting in reduced transcription of its target genes such as cyclin E that promotes cell-proliferation and dIAP1 that inhibits cell death [20]. Loss-offunction mutations in hpo, wts, sav, or mats induce up-regulation of Yki activity, increase expression of cyclin E and dIAP1, and exhibit tumor-like overgrowth [21-26]. Similarly in mammals, MST1/2 binds to WW45 to phosphorylate and activate the complex of Mob1/2 and LATS1/2. In addition mammalian homologue of Yki, YAP and TAZ also function as transcriptional co-activators and promote cell proliferation [13,27-32].