title: The Hippo pathway in disease and therapy: cancer and beyond.
abstract: The Hippo tumour suppressor pathway co-ordinates cell proliferation, cell death and cell differentiation to regulate tissue growth control. In mammals, a conserved core Hippo signalling module receives signal inputs on different levels to ensure the proper regulation of YAP/TAZ activities as transcriptional co-activators. While the core module members MST1/2, Salvador, LATS1/2 and MOB1 have been attributed tumour suppressive functions, YAP/TAZ have been mainly described to have oncogenic roles, although some reports provided evidence supporting growth suppressive roles of YAP/TAZ in certain cancer settings. Intriguingly, mammalian Hippo signalling is also implicated in non-cancer diseases and plays a role in tissue regeneration following injury. Cumulatively, these findings indicate that the pharmacological inhibition or activation of the Hippo pathway could be desirable depending on the disease context. In this review, we first summarise the functions of the mammalian Hippo pathway in tumour formation, and then discuss non-cancer diseases involving Hippo signalling core components with a specific focus on our current understanding of the non-cancer roles of MST1/2 and YAP/TAZ. In addition, the pros and cons of possible pharmacological interventions with Hippo signalling will be reviewed, with particular emphasis on anti-cancer drug development and regenerative medicine.
authors.affiliation: Tumour Suppressor Signalling Networks laboratory, UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Gomez
authors.affiliation: Tumour Suppressor Signalling Networks laboratory, UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT London, UK.
authors.forename: Valenti
authors.initials: V
authors.lastname: Gomez
authors.affiliation: Tumour Suppressor Signalling Networks laboratory, UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT London, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
keywords: Cancer; Hippo signalling cascade; LATS; MOB1; MST; Protein kinases; Protein-protein interactions; Scaffolding proteins; Therapy; Tissue repair
references.citation: Cell Biosci. 2013 Aug 28;3(1):32
references.pmid: 23985307
references.citation: Development. 2013 Dec;140(23):4683-90
references.pmid: 24255096
references.citation: Cancer Sci. 2013 Oct;104(10):1271-7
references.pmid: 23829894
references.citation: J Clin Invest. 2003 May;111(10):1463-74
references.pmid: 12750396
references.citation: Blood. 2012 Apr 12;119(15):3450-7
references.pmid: 22294732
references.citation: Cell Res. 2014 Mar;24(3):331-43
references.pmid: 24458094
references.citation: Circ Res. 2014 Jan 31;114(3):454-68
references.pmid: 24276085
references.citation: Clin Cancer Res. 2013 Sep 15;19(18):4925-30
references.pmid: 23797907
references.citation: J Biol Chem. 2009 May 22;284(21):14347-58
references.pmid: 19324876
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13839-44
references.pmid: 23918388
references.citation: PLoS One. 2013;8(3):e58697
references.pmid: 23527007
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17474-9
references.pmid: 24082083
references.citation: Cell. 2012 Aug 17;150(4):780-91
references.pmid: 22863277
references.citation: Cancer Res. 2009 Feb 1;69(3):1089-98
references.pmid: 19141641
references.citation: Sci Signal. 2011 Oct 25;4(196):ra70
references.pmid: 22028467
references.citation: Breast Cancer Res. 2012 Dec 05;14(6):326
references.pmid: 23216692
references.citation: Curr Opin Cell Biol. 2013 Apr;25(2):247-53
references.pmid: 23312716
references.citation: Oncogene. 2014 Mar 13;33(11):1468-74
references.pmid: 23542177
references.citation: J Biol Chem. 2009 May 15;284(20):13355-13362
references.pmid: 19324877
references.citation: Sci Rep. 2013 Oct 02;3:2650
references.pmid: 24084849
references.citation: Nat Rev Mol Cell Biol. 2006 Apr;7(4):253-64
references.pmid: 16607288
references.citation: Nat Rev Cancer. 2013 Jun;13(6):412-24
references.pmid: 23640210
references.citation: Curr Biol. 2012 Sep 11;22(17):1587-94
references.pmid: 22840515
references.citation: Genes Dev. 2013 Feb 15;27(4):355-71
references.pmid: 23431053
references.citation: Int J Cardiol. 2013 Oct 9;168(4):3291-9
references.pmid: 23647599
references.citation: Oncogene. 2013 Apr 25;32(17):2220-9
references.pmid: 22689061
references.citation: Cell Res. 2014 Feb;24(2):137-8
references.pmid: 24418760
references.citation: Cell. 2011 Nov 11;147(4):759-72
references.pmid: 22078877
references.citation: Cancer Res. 2008 Apr 15;68(8):2789-94
references.pmid: 18413746
references.citation: Semin Cell Dev Biol. 2012 Sep;23(7):770-84
references.pmid: 22898666
references.citation: J Alzheimers Dis. 2011;23(4):689-99
references.pmid: 21178287
references.citation: PLoS One. 2013 Sep 09;8(9):e73874
references.pmid: 24040101
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6
references.pmid: 20080598
references.citation: Nat Cell Biol. 2008 Jul;10(7):837-48
references.pmid: 18568018
references.citation: J Clin Invest. 2012 Dec;122(12):4505-18
references.pmid: 23143302
references.citation: Cell. 2013 Aug 29;154(5):1047-1059
references.pmid: 23954413
references.citation: Nat Rev Drug Discov. 2014 Jan;13(1):63-79
references.pmid: 24336504
references.citation: Genes Dev. 2010 Jun 1;24(11):1106-18
references.pmid: 20516196
references.citation: J Biol Chem. 2008 Feb 29;283(9):5496-509
references.pmid: 18158288
references.citation: Trends Cell Biol. 2001 May;11(5):220-30
references.pmid: 11316611
references.citation: Hum Mol Genet. 2012 May 1;21(9):2054-67
references.pmid: 22286172
references.citation: Science. 2011 Apr 22;332(6028):458-61
references.pmid: 21512031
references.citation: Nat Med. 2012 Oct;18(10):1511-7
references.pmid: 23001183
references.citation: Mol Cell Proteomics. 2014 Jan;13(1):119-31
references.pmid: 24126142
references.citation: Cell. 2013 Nov 7;155(4):948-62
references.pmid: 24183448
references.citation: Nature. 2011 Jun 08;474(7350):179-83
references.pmid: 21654799
references.citation: Nat Commun. 2014;5:3315
references.pmid: 24525530
references.citation: Am J Physiol Cell Physiol. 2014 May 1;306(9):C805-18
references.pmid: 24573087
references.citation: Chembiochem. 2013 Jul 8;14(10):1218-25
references.pmid: 23780915
references.citation: Nature. 2014 Jan 23;505(7484):495-501
references.pmid: 24390350
references.citation: Cell Cycle. 2009 Jan 1;8(1):49-57
references.pmid: 19106601
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10
references.pmid: 16894141
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1437-42
references.pmid: 20080689
references.citation: J Biol Chem. 2012 Jun 22;287(26):22089-98
references.pmid: 22544757
references.citation: Trends Pharmacol Sci. 2013 Jul;34(7):393-400
references.pmid: 23725674
references.citation: Nature. 2013 Jan 3;493(7430):106-10
references.pmid: 23178811
references.citation: Nat Commun. 2012;3:1098
references.pmid: 23033074
references.citation: Curr Biol. 2013 Feb 4;23(3):R110-2
references.pmid: 23391384
references.citation: Cancer Cell. 2014 Feb 10;25(2):166-80
references.pmid: 24525233
references.citation: BMC Biol. 2013 Feb 01;11:12
references.pmid: 23374633
references.citation: Trends Cell Biol. 2012 Feb;22(2):88-96
references.pmid: 22153608
references.citation: Curr Biol. 2008 Mar 11;18(5):311-21
references.pmid: 18328708
references.citation: Cell Signal. 2014 Aug;26(8):1657-67
references.pmid: 24747552
references.citation: Cell. 2012 Dec 21;151(7):1457-73
references.pmid: 23245941
references.citation: EMBO J. 2009 May 6;28(9):1319-31
references.pmid: 19339990
references.citation: J Biol Chem. 2010 Nov 26;285(48):37159-69
references.pmid: 20858893
references.citation: Cell. 2007 Sep 21;130(6):1120-33
references.pmid: 17889654
references.citation: J Biochem. 2011 Aug;150(2):199-208
references.pmid: 21586534
references.citation: Genes Dev. 2010 Nov 1;24(21):2383-8
references.pmid: 21041407
references.citation: Cancer Cell. 2009 Nov 6;16(5):425-38
references.pmid: 19878874
references.citation: Genes Dev. 2010 Jan 1;24(1):72-85
references.pmid: 20048001
references.citation: J Invest Dermatol. 2014 Feb;134(2):518-525
references.pmid: 24108406
references.citation: Mol Biol Cell. 2014 May;25(10):1676-85
references.pmid: 24648494
references.citation: Nat Rev Mol Cell Biol. 2012 Sep;13(9):591-600
references.pmid: 22895435
references.citation: Cancer Res. 2011 Apr 1;71(7):2728-38
references.pmid: 21349946
references.citation: Cell. 2011 Mar 4;144(5):782-95
references.pmid: 21376238
references.citation: Nat Cell Biol. 2014 Apr;16(4):357-66
references.pmid: 24658687
references.citation: Genes Dev. 2008 Jul 15;22(14):1962-71
references.pmid: 18579750
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2394-9
references.pmid: 22308401
references.citation: Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12066-71
references.pmid: 23818595
references.citation: Nat Med. 2013 Nov;19(11):1478-88
references.pmid: 24141421
references.citation: Circ Res. 2008 Nov 21;103(11):1309-18
references.pmid: 18927464
references.citation: Chem Biol. 2012 Aug 24;19(8):955-62
references.pmid: 22884261
references.citation: Biochem Soc Trans. 2012 Feb;40(1):124-8
references.pmid: 22260677
references.citation: Cell. 2009 Nov 25;139(5):871-90
references.pmid: 19945376
references.citation: Biochem Biophys Res Commun. 2010 Mar 19;393(4):619-24
references.pmid: 20153295
references.citation: J Cell Sci. 2012 Dec 15;125(Pt 24):6009-19
references.pmid: 23038772
references.citation: Biofactors. 2009 Jul-Aug;35(4):338-45
references.pmid: 19484742
references.citation: Biochem J. 2013 Jun 1;452(2):281-91
references.pmid: 23485012
references.citation: Nat Commun. 2013;4:2976
references.pmid: 24356468
references.citation: Biochem J. 2009 Feb 15;418(1):93-101
references.pmid: 18986304
references.citation: J Biol Chem. 2013 Feb 8;288(6):3977-88
references.pmid: 23275380
references.citation: Nat Biotechnol. 2014 Jun;32(6):551-3
references.pmid: 24681508
references.citation: Cell Cycle. 2007 Dec 1;6(23):2906-12
references.pmid: 18000400
references.citation: Semin Cell Dev Biol. 2012 Sep;23(7):785-93
references.pmid: 22659496
references.citation: Science. 2013 Nov 8;342(6159):737-40
references.pmid: 24114784
references.citation: Mol Cell Biol. 2008 Apr;28(7):2426-36
references.pmid: 18227151
references.citation: J Immunol. 2014 Feb 15;192(4):1525-35
references.pmid: 24453252
references.citation: PLoS One. 2013;8(3):e59622
references.pmid: 23544078
references.citation: Mol Syst Biol. 2013 Dec 22;9:713
references.pmid: 24366813
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20321-6
references.pmid: 19073936
references.citation: Genes Dev. 2012 Jun 15;26(12):1300-5
references.pmid: 22677547
references.citation: J Exp Med. 2012 Apr 9;209(4):741-59
references.pmid: 22412158
references.citation: Mol Cell Biol. 2012 Dec;32(24):5116-28
references.pmid: 23071096
references.citation: Development. 2008 Dec;135(24):4059-69
references.pmid: 19004856
references.citation: Genes Dev. 2012 Oct 1;26(19):2138-43
references.pmid: 22972936
references.citation: Exp Eye Res. 2013 Aug;113:66-73
references.pmid: 23727052
references.citation: Dev Dyn. 2012 Jan;241(1):3-15
references.pmid: 22174083
references.citation: Dev Cell. 2013 Jul 29;26(2):188-94
references.pmid: 23850191
references.citation: Nat Rev Cancer. 2009 Apr;9(4):265-73
references.pmid: 19262571
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2441-50
references.pmid: 22891335
references.citation: Cell Signal. 2011 Sep;23(9):1433-40
references.pmid: 21539912
references.citation: Curr Biol. 2007 Dec 4;17(23):2054-60
references.pmid: 17980593
references.citation: ACS Nano. 2014 Mar 25;8(3):2033-47
references.pmid: 24483337
references.citation: Curr Opin Cell Biol. 2014 Apr;27:126-35
references.pmid: 24508914
references.citation: Brain Res. 2013 Oct 16;1535:137-47
references.pmid: 23998984
references.citation: J Hum Genet. 2011 Apr;56(4):270-6
references.pmid: 21289630
references.citation: Proc Natl Acad Sci U S A. 2013 May 7;110(19):7732-7
references.pmid: 23620511
references.citation: Nat Rev Cancer. 2013 Apr;13(4):246-57
references.pmid: 23467301
references.citation: BMC Cancer. 2014 Feb 22;14:119
references.pmid: 24559095
references.citation: Sci Signal. 2013 Nov 19;6(302):rs15
references.pmid: 24255178
references.citation: Blood. 2012 Apr 12;119(15):3458-68
references.pmid: 22174160
references.citation: Gastroenterology. 2013 Jun;144(7):1543-53, 1553.e1
references.pmid: 23454691
references.citation: Trends Pharmacol Sci. 2013 Oct;34(10):581-9
references.pmid: 24051213
references.citation: Circ Res. 2007 May 11;100(9):1344-52
references.pmid: 17395874
references.citation: Nat Cell Biol. 2013 Jan;15(1):61-71
references.pmid: 23263283