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  • br Methods br Acknowledgements We are grateful

    2021-09-26


    Methods
    Acknowledgements We are grateful to Eric Olson for providing Yap/Taz floxed mice, and to members of the Epstein lab for helpful comments and advice. This work was supported by NIH R01 HL118768, R35 HL140018, the Cotswold Foundation and the WW Smith Endowed Chair to J.A.E.
    The Hippo Signaling Network The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. It was first discovered in Drosophila through the identification and characterization of genes that, when mutated, cause severe overgrowth phenotypes [1]. Hippo signaling is highly conserved among animals and dysregulation of the pathway has been linked to many human cancers [2]. One remarkable feature of Hippo signaling is its role as an integrator of growth control signals. Hippo signaling is influenced by, or crosstalks with, multiple pathways that respond to growth factors, that promote growth linked to positional information, or that influence growth in response to nutritional and metabolic status 3, 4, 5. Hippo signaling is also affected by contacts with neighboring cells and the extracellular matrix (ECM) and by mechanical forces. In this review we first briefly describe new insights into core components of the Hippo pathway and then focus on recent discoveries that have enhanced our understanding of the cellular organization of the Hippo pathway and its regulation by cell junctions, the MG-262 cytoskeleton, and mechanical force.
    Expansion of the Hippo Core Hippo signaling regulates growth by controlling the localization of a transcriptional coactivator protein that in Drosophila is known as Yorkie (Yki) 6, 7, 8. Transcriptional activation by Yki, which is achieved in part by recruiting chromatin- and histone-modifying complexes 9, 10, 11, leads to increased growth. Yki is downregulated through phosphorylation by the kinase Warts (Wts), which promotes cytoplasmic localization of Yki 6, 7. As most upstream inputs of Hippo signaling affect Wts and Wts directly regulates Yki, Wts serves as a central regulatory node within the Hippo pathway. Wts is regulated in several ways, including phosphorylation by the kinase Hippo (Hpo) 12, 13, 14, 15, 16, and regulation of Wts abundance [17], Wts localization 18, 19, and Wts interaction with cofactors and inhibitors 20, 21, 22, 23, 24. Activation of Wts is dependent on two additional core components of the Hippo pathway: Mob-as-tumor suppressor (Mats), which is a Wts cofactor [23], and Salvador (Sav) 25, 26, which promotes Wts activation by acting as a scaffold that links Wts to Hpo 12, 13, 14, 15, 16. The four proteins that regulate Yki, Hpo, Wts, Sav, and Mats have been generally considered as the ‘core’ of the Hippo network (Figure 1A). Mammals have an analogous Hippo network that includes the core components identified in Drosophila (although assigned different names). However, mammalian Hippo signaling has greater complexity and includes two Wts homologs, LATS1 and LATS2, two Hippo homologs, MST1 and MST2, and two Yki homologs, YAP and TAZ (Figure 1B) 2, 3. As in Drosophila, LATS proteins are the major, although not exclusive, regulators of YAP and TAZ. In mammals, YAP and TAZ localization as well as their stability are regulated through LATS-dependent and LATS-independent processes [3]. Moreover, several ubiquitin ligases that influence LATS stability have been identified 27, 28, 29, 30, 31, 32. LATS kinases are members of a larger family of protein kinases, the Nuclear Dbf2-related kinases, and two other family members, NDR1 and NDR2, have recently been reported to phosphorylate Yap and regulate Yap activity [33]. Recent studies have also led to the identification, in both Drosophila and mammals, of multiple MAP4K-type kinases (which, like Hpo/Mst, are within the Ste20 family of protein kinases) that phosphorylate and activate Wts and LATS 34, 35, 36, 37. The identification of these additional core components of the pathway explains some instances of MST-independent regulation of LATS and emphasizes that different inputs into the Hippo pathway could act through regulation of distinct kinases.