Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press The Hippo Pathway Kieran F. Harvey1 and Iswar K. Hariharan2 1Peter MacCallum Cancer Centre, East Melbourne 3002, Australia 2University of California, Berkeley, Berkeley, California 94720 Correspondence: [email protected] The Hippo pathway (Fig. 1), also known as the Salvador- Johnson 2011; Zhao et al. 2011). Many components of Warts-Hippo pathway, regulates tissue growth in a wide the pathway were identified as a result of mutations in variety of organisms (Harvey and Tapon 2007; Grusche the fruit fly Drosophila melanogaster that resulted in tis- et al. 2010; Oh and Irvine 2010; Pan 2010; Halder and sue overgrowth (Table 1). The pathway is conserved in CRB FJ FJ EX FT LFT SAR Kibra DCO STRIPAK LFT DS MER TAO1 RASSF APP D JUB AJ HPO ZYX MATS SAV WTS αPKC LGL 14-3-3 SJ WBP2 SCRIB YKI DLG MOP YKI Target MAD TSH HTH SD genes Nucleus Figure 1. The Drosophila Hippo pathway. Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy W. Thorner Additional Perspectives on Signal Transduction available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011288 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011288 1 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press K.F. Harvey and I.K. Hariharan Table 1. Components of the Drosophila melanogaster Salvador- Warts (WTS; also known as LATS) (Justice et al. 1995; Xu Warts-Hippo pathway and their human homologues et al. 1995)—and two other proteins—Salvador (SAV) Drosophila Human (Kango-Singh et al. 2002; Tapon et al. 2002) and Mob as Upstream Tumor Suppressor (MATS) (Lai et al. 2005). HPO func- Fat (FT) FAT1—FAT4 tions upstream of WTS and can directly phosphorylate it. Dachsous (DS) DCHS1 and DCHS2 Mutations that inactivate any of these four proteins result Discs overgrown (DCO) CK11 and CK1d in tissue overgrowth. The first indication that some of these Lowfat (LFT) LIX1 and LIX1L proteins might function in a pathway was the observation Four-jointed (FJ) FJX1 that sav and wts mutants display similar phenotypic abnor- Dachs (D) ? Approximated (APP) ZDHHC9, ZDHHC14 and ZDHHC18 malities and that the two proteins can interact with each Zyxin (ZYX) Zyxin, LPP and TRIP6 other (Tapon et al. 2002). More recently it has been shown Merlin (MER) Merlin (also known as NF2) that activity of this module can be regulated by RASSF, a Expanded (EX) Willin/FRMD6 and FRMD1 scaffold protein that promotes tissue growth by recruiting Kibra Kibra the serine-threonine phosphatase complex STRIPAK to in- Crumbs (CRB) CRB1—CRB3 hibit HPO autophosphorylation, and hence HPO activity Lethal giant larvae (LGL) LGL1 and LGl2 (Ribeiro et al. 2010). Discs large (DLG) DLG1—DLG4 Scribble (SCRIB) SCRIB The main output of the module involves the transcrip- aPKC aPKCi and aPKCz tional coactivator Yorkie (YKI) (Huang et al. 2005). Phos- STRIPAK (PP2A) PP2A (STRIPAK) phorylation of YKI by WTS induces binding of 14-3-3 RASSF RASSF1-RASSF6 proteins to YKI that limit YKI activity by preventing nu- Myopic (MOP) HD-PTP clear accumulation. Phosphatases that counter the activity JUB Ajuba, LIMD1, WTIP of WTS have not been discovered but the Myopic (MOP) TAO1 TAO1—TAO3 tyrosine phosphatase regulates YKI activity, repressing it Core (Gilbert et al. 2011). YKI promotes tissue growth by in- Hippo (HPO) MST1 and MST2 creasing expression of positive regulators of cell growth and Salvador (SAV) SAV1 Mats (MTS) MOBKL1A and MOBKL1AB inhibitors of apoptosis. YKI, itself does not bind DNA but Warts (WTS) LATS1 and LATS2 functions together with several transcription factors, in- Downstream cluding Scalloped (SD; the homolog of TEAD transcrip- Yorkie (YKI) YAP and TAZ tion factors in vertebrates), Homothorax (HTH), Teashirt WBP2 WBP2 (TSH), and Mothers against DPP (MAD). Transcriptional Scalloped (SD) TEAD1—TEAD4 regulatory proteins such as WBP2 also control Hippo- MAD SMADs pathway-dependent tissue growth (Zhang et al. 2011). TSH TSHZ1—TSHZ3 WBP2 and other as-yet-unidentified proteins have been HTH MEIS1—MEIS3 predicted to interact with YKI via its WW domains, which are important for YKI’s transcription activation function (Oh and Irvine 2010). vertebrates, including mammals (Fig. 2), and changing the The HPO and WTS kinases appear to receive multiple activity of the pathway can result in dramatic changes in the inputs. The first upstream regulators to be discovered were size of certain organs, most notably the liver (Pan 2010; the Band 4.1 proteins Expanded (EX) and MER (Hama- Halder and Johnson 2011). In addition to its role in regu- ratoglu et al. 2006). These function together with the WW- lating tissue growth, the pathway has been implicated in the domain-containing protein Kibra to activate the core ki- control of other biological processes, such as cell-fate de- nase cassette by an unknown mechanism. EX is also termination, mitosis, and pluripotency. Deregulation of thought to repress YKI by physical interaction and seques- Hippo pathway activity has been reported in many human tration. The Fat/Dachsous branch of the pathway consists cancers. The human homolog of D. melanogaster Merlin of the atypical cadherins Fat (FT) and Dachsous (DS) as (MER), also known as Neurofibromatosis Type 2 (NF2) is a well as the downstream effector proteins Discs overgrown bona fide tumor suppressor, while altered activity of several (DCO, a serine-threonine kinase also known as casein ki- Hippo pathway components has been implicated in human nase 11), Dachs (D, an atypical myosin), Approximated tumorigenesis (Harvey and Tapon 2007). (APP, a palmitoyltransferase), Lowfat (LFT), and Zyxin At the core of the pathway is a module composed of two (ZYX) (Grusche et al. 2010; Rauskolb et al. 2011). The kinases—Hippo (HPO) (Harvey et al. 2003; Jia et al. 2003; Fat/Dachsous branch impinges on pathway activity by Pantalacci et al. 2003; Udan et al. 2003; Wu et al. 2003) and modulating the abundance of WTS and also modulates 2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011288 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Hippo Pathway PALS1 CRB3 PATJ Willin AMOTs TJ YAP/TAZ Kibra MER RASSF TAO1 α PP2A -Catenin AJ 14-3-3 YAP/TAZ MST1/2 MOB SAV LATS1/2 Ajuba WBP2 CK1 β-TRCP YAP/TAZ 14-3-3 YAP/TAZ Target SMAD1-3 TEAD1-4 genes Nucleus Figure 2. The mammalian Hippo pathway. the Kibra-EX-MER branch by regulating EX levels. The atypical protein kinase C (aPKC). In mammalian epithe- sterile 20-like kinase, TAO1, phosphorylates and activates lial cells, several other junctional proteins regulate Hippo HPO (MST1/2 in mammals) although it is unclear wheth- pathway activity (see Table 2), including angiomotin and er TAO1 activity is regulated (Boggiano et al. 2011; Poon et al. 2011). Table 2. Components of the human Salvador-Warts-Hippo pathway Increasing evidence underlines the importance of cell and their Drosophila melanogaster homologs junctions for regulation of Hippo pathway activity. In Human Drosophila D. melanogaster epithelial cells, many Hippo pathway pro- Upstream teins reside, at least partially, at the sub-apical region (SAR), a-Catenin a-Catenin adherens junction (AJ) or septate junction (SJ). Examples PATJ Discs lost of such junctional proteins include the AJ protein Jub and PALS1 Stardust the apical-basal polarity proteins Discs large (DLG), Lethal AMOTs ? giant larvae (LGL), Scribble (SCRIB), Crumbs (CRB), and b-TRCP Slimb Cite this article as Cold Spring Harb Perspect Biol 2012;4:a011288 3 Downloaded from http://cshperspectives.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press K.F. Harvey and I.K. Hariharan a-catenin (Schlegelmilch et al. 2011; Zhao et al. 2011). The Lai ZC, Wei X, Shimizu T,Ramos E, Rohrbaugh M, Nikolaidis N, Ho LL, Hippo pathway may therefore help couple tissue growth to Li Y.2005. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120: 675–685. mechanical stresses or cell–cell contact, which might be im- Oh H, Irvine KD. 2010. Yorkie: The final destination of Hippo signaling. portant for organ size regulation. Trends Cell Biol 20: 410–417. Pan D. 2010. 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