Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Jan 1;30(1):1-17.
doi: 10.1101/gad.274027.115.

Mechanisms of Hippo pathway regulation

Zhipeng Meng  1 , Toshiro Moroishi  1 , Kun-Liang Guan  1
Affiliations
Review

Mechanisms of Hippo pathway regulation

Zhipeng Meng et al. Genes Dev. .

Abstract

The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell-cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

Keywords: LATS; MAP4K; MST; TAZ; TEAD; YAP.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
The core Hippo pathway in mammals and Drosophila. (A) The mammalian Hippo pathway. When the Hippo pathway is inactive, YAP and TAZ are unphosphorylated and localized in the nucleus to compete with VGLL4 for TEAD binding and activation of gene transcription. The Hippo pathway can be activated by TAO kinases, which phosphorylate MST1/2 at its activation loop. MST1/2 in turn phosphorylate LATS1/2, facilitated by scaffold proteins SAV1, MOB1A/B, and NF2. MAP4K4/6/7 and MAP4K1/2/3/5 also phosphorylate and activate LATS1/2. Phosphorylation of LATS1/2 by MAP4K4/6/7 requires NF2 (also known as Mer). Activated LATS1/2 phosphorylate YAP and TAZ, leading to 14-3-3-mediated YAP and TAZ cytoplasmic retention and SCF-mediated YAP and TAZ degradation. (B) The Drosophila Hippo pathway. Active Yki competes Tgi to interact with Sd in the nucleus and activates the transcription of Sd target genes. When Hpo is activated by Tao kinase or dimerization, it phosphorylates and activates Wts with the assistance of the scaffold proteins Sav and Mats as well as Mer. It is unclear whether Msn and Hppy require Mer and Sav to phosphorylate and activate Wts. Active Wts phosphorylates and inactivates Yki, leading to 14-3-3-mediated Yki cytoplasmic retention.
Figure 2.
Figure 2.
Regulation of the Hippo pathway by upstream signals. Cyclic stretch or high extracellular matrix stiffness inhibits LATS1/2 phosphorylation through Rho-GTPases and JNK1/2. G-protein-coupled receptors (GPCRs) can either activate or suppress LATS1/2 depending on the types of the Gα proteins involved. The LATS1/2 activation is also controlled by cell polarity and architecture through KIBRA/NF2, adherens junctions (AJ), and tight junctions (TJ). Energy status modulates YAP and TAZ activity via AMPK. Cell cycle affects YAP and TAZ through either LATS1/2- or CDK1-mediated protein phosphorylation.
Figure 3.
Figure 3.
A proposed sequential phosphorylation model of LATS activation by MST. First, upon activation MST1/2 autophosphorylates its linker region (which is between the catalytic domain and the SARAH domain) at multiple sites to create a phosphor-docking site for MOB1. Second, phosphorylated MST binds to MOB1 and changes MOB1 from an autoinhibitory state to a conformation that is open for LATS binding. Third, LATS binds to MOB1 potentially through recruitment by NF2 to the MST–SAV1 complex at the plasma membrane. Fourth, the formation of the MST–MOB1–LATS complex enables MST to phosphorylate MOB1's N-terminal tail at Thr12 (T12) and Thr35 (T35) and phosphorylate LATS at its hydrophobic motif (HM). Fifth, the phosphorylated N-terminal tail of MOB1 competes with the phosphoMST linker for the same binding site on MOB1 and thus releases MOB1 and LATS from MST. Sixth, phosphoMOB1 allosterically enhances LATS autophosphorylation at its activation loop (AL) and thus promotes LATS activation.
Figure 4.
Figure 4.
Domain structure and protein interaction of LATS1/2. Kinase activity of LATS1/2 is primarily regulated by MST1/2 and MAP4Ks through the hydrophobic motif phosphorylation followed by autophosphorylation of the activation loop of LATS1/2. There is a putative ubiquitin-associated domain (UBA) in the N termini of the kinases, and several E3 ubiquitination ligases, such as ITCH, SIAH-2, NEDD4, and DCAF1, are known to regulate LATS1/2 protein stability. The binding of MOB, ZYXIN, LIMD1 with the protein-binding domain (PBD) can also regulate LATS1/2 kinase activity or availability. YAP and TAZ interact with LATS1/2 through the PPxY motifs of LATS1/2. Aurora kinases A/B phosphorylate LATS2 and affect its subcellular locations. (PA repeat) Proline–alanine residue repeat; (AL) activation loop; (HM) hydrophobic motif.
Figure 5.
Figure 5.
The transcription program of the Hippo pathway. YAP and TAZ bind to TEAD at promoters or enhancers of the target genes to regulate transcription activation or pause release. The TEAD target genes are involved in a variety of physiological processes, such as cell survival, proliferation, differentiation, migration, and invasion.
See this image and copyright information in PMC

References

    1. Aerne BL, Gailite I, Sims D, Tapon N. 2015. Hippo stabilises its adaptor salvador by antagonising the HECT ubiquitin ligase Herc4. PLoS One 10: e0131113. - PMC - PubMed
    1. Anastas JN, Moon RT. 2013. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13: 11–26. - PubMed
    1. Antonescu CR, Le Loarer F, Mosquera JM, Sboner A, Zhang L, Chen CL, Chen HW, Pathan N, Krausz T, Dickson BC, et al. 2013. Novel YAP1–TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer 52: 775–784. - PMC - PubMed
    1. Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S. 2013. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154: 1047–1059. - PubMed
    1. Ardestani A, Paroni F, Azizi Z, Kaur S, Khobragade V, Yuan T, Frogne T, Tao W, Oberholzer J, Pattou F, et al. 2014. MST1 is a key regulator of β cell apoptosis and dysfunction in diabetes. Nat Med 20: 385–397. - PMC - PubMed

Publication types

MeSH terms

Substances