Fat/Dachsous Signaling Promotes Drosophila Wing Growth by Regulating the Conformational State of the NDR Kinase Warts

Abstract

Nuclear Dbf2-related (NDR) kinases play a central role in limiting growth in most animals. Signals that promote growth do so in part by suppressing the activation of NDR kinases by STE20/Hippo kinases. Here, we identify another mechanism for downregulating NDR kinase activity. Specifically, we show that activity of the Drosophila NDR kinase Warts in the developing wing depends on its transition from an inactive, "closed" conformation to a potentially active, "open" conformation mediated by Mats, a conserved Mps1-binder (Mob) protein. Further, we show that signaling interactions between the protocadherins Fat and Dachsous, organized by the morphogens Wingless and Decapentaplegic, suppress Warts by acting via the atypical myosin Dachs to inhibit or reverse this transition. The regulation of Warts conformation by Mats, Fat/Dachsous signaling, and Dachs appears independent of Warts phosphorylation by Hippo kinase, establishing a precedent for the control of NDR kinases, and hence growth, by distinct allosteric and phosphorylation mechanisms.