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Review
. 2018 Mar;51(3):134-142.
doi: 10.5483/bmbrep.2018.51.3.027.

Upstream Paths for Hippo Signaling in Drosophila Organ Development

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Free PMC article
Review

Upstream Paths for Hippo Signaling in Drosophila Organ Development

Kwang-Wook Choi. BMB Rep. .
Free PMC article

Abstract

Organ growth is fundamental to animal development. One of major mechanisms for growth control is mediated by the conserved Hippo signaling pathway initially identified in Drosophila. The core of this pathway in Drosophila consists of a cascade of protein kinases Hippo and Warts that negatively regulate transcriptional coactivator Yorkie (Yki). Activation of Yki promotes cell survival and proliferation to induce organ growth. A key issue in Hippo signaling is to understand how core kinase cascade is activated. Activation of Hippo kinase cascade is regulated in the upstream by at least two transmembrane proteins Crumbs and Fat that act in parallel. These membrane proteins interact with additional factors such as FERM-domain proteins Expanded and Merlin to modulate subcellular localization and function of the Hippo kinase cascade. Hippo signaling is also influenced by cytoskeletal networks and cell tension in epithelia of developing organs. These upstream events in the regulation of Hippo signaling are only partially understood. This review focuses on our current understanding of some upstream processes involved in Hippo signaling in developing Drosophila organs. [BMB Reports 2018; 51(3): 134-142].

Conflict of interest statement

CONFLICTS OF INTEREST

The authors have no conflicting interests.

Figures

Fig. 1
Fig. 1
Upstream pathways for Hippo signaling. Hippo signaling is regulated by two upstream events. (A) Transmembrane protein Ft activates Wts by inhibiting Dachs. Dco promotes Ft activity by phosphorylation. Ft also regulates Ex localization. (B) Crb binds to Ex. Ex, Mer, and Kibra function together to activate the Hippo kinase cascade. (C) The core kinase cascade. Hpo, together with Sav, activates Wts through phosphorylation. Activated Wts phosphorylates Yki to block its nuclear entry.
Fig. 2
Fig. 2
Overview of the Hippo signaling pathway in Drosophila. Key steps of Hippo signaling. (1) Membrane proteins Ft and Crb regulate junctional localization of Dachs and Ex-Mer-Kibra, respectively. (2) Ex-Mer-Kibra function together to activate the Hippo kinase cascade. Mer and Kibra can form a complex at cell junction (Junctional complex) and at apical medial region (Medial complex). Ex binds to Schip1 which then promotes Tao-1 kinase activity for Hpo phosphorylation. (3) Hpo-Wts core kinase cascade. Activated Wts phosphorylates Yki to block its nuclear entry. F-actin formation and Yki activation are negatively regulated by capping proteins (Cp) and Tsr/cofilin. (4) When Wts is inactive, Yki induces target gene expression to promote cell proliferation and cell survival.
Fig. 3
Fig. 3
Role of actin cytoskeleton in Hippo signaling. Cell adhesion is regulated by Ecad, β-catenin (βCat), and α-Catenin (αCat) at the adherens junction. α(Cat) interacts with actomyosin networks. Under cell tension, Jub is apically localized with Wts to inactivate Wts, increasing Yki activity for growth. Fast growth reduces cytoskeletal tension by feedback to decrease junctional localization of Jub and Wts, thus decreasing Yki activity.

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