title: Molecular insights into NF2/Merlin tumor suppressor function.
abstract: The FERM domain protein Merlin, encoded by the NF2 tumor suppressor gene, regulates cell proliferation in response to adhesive signaling. The growth inhibitory function of Merlin is induced by intercellular adhesion and inactivated by joint integrin/receptor tyrosine kinase signaling. Merlin contributes to the formation of cell junctions in polarized tissues, activates anti-mitogenic signaling at tight-junctions, and inhibits oncogenic gene expression. Thus, inactivation of Merlin causes uncontrolled mitogenic signaling and tumorigenesis. Merlin's predominant tumor suppressive functions are attributable to its control of oncogenic gene expression through regulation of Hippo signaling. Notably, Merlin translocates to the nucleus where it directly inhibits the CRL4(DCAF1) E3 ubiquitin ligase, thereby suppressing inhibition of the Lats kinases. A dichotomy in NF2 function has emerged whereby Merlin acts at the cell cortex to organize cell junctions and propagate anti-mitogenic signaling, whereas it inhibits oncogenic gene expression through the inhibition of CRL4(DCAF1) and activation of Hippo signaling. The biochemical events underlying Merlin's normal function and tumor suppressive activity will be discussed in this Review, with emphasis on recent discoveries that have greatly influenced our understanding of Merlin biology.
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: cooperj1@mskcc.org.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cooper
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: F-Giancotti@ski.mskcc.org.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
mesh_terms: D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D025581:Neurofibromin 2 / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
chemical_list: D025581:Neurofibromin 2
keywords: CRL4 E3 ubiquitin ligase; Contact inhibition; DDB1 and Cul4-Associated Factor 1; Hippo signaling pathway; Merlin; Neurofibromatosis Type 2
references.citation: J Neurosci Res. 1999 Dec 1;58(5):706-16
references.pmid: 10561699
references.citation: Mol Cell. 2013 Nov 7;52(3):459-67
references.pmid: 24140421
references.citation: Hum Mol Genet. 2003 Jun 1;12(11):1211-21
references.pmid: 12761036
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 7;107(36):15810-5
references.pmid: 20798049
references.citation: Mol Cell. 2012 Nov 30;48(4):572-86
references.pmid: 23063525
references.citation: Nat Cell Biol. 2006 Jan;8(1):27-36
references.pmid: 16341207
references.citation: Oncogene. 1996 Sep 19;13(6):1239-47
references.pmid: 8808698
references.citation: Nat Rev Cancer. 2007 Mar;7(3):182-91
references.pmid: 17318211
references.citation: Nat Rev Mol Cell Biol. 2002 Aug;3(8):586-99
references.pmid: 12154370
references.citation: Cell. 2014 Jan 16;156(1-2):134-45
references.pmid: 24412650
references.citation: Nucleic Acids Res. 2012 Aug;40(15):7332-46
references.pmid: 22570418
references.citation: Dev Cell. 2001 Jul;1(1):63-72
references.pmid: 11703924
references.citation: Dev Cell. 2010 Oct 19;19(4):491-505
references.pmid: 20951342
references.citation: Cell. 2006 Jan 13;124(1):105-17
references.pmid: 16413485
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Hum Mol Genet. 2002 Sep 15;11(19):2269-78
references.pmid: 12217955
references.citation: Cell. 2013 Sep 12;154(6):1342-55
references.pmid: 24012335
references.citation: Oncogene. 2004 Jan 15;23(2):580-7
references.pmid: 14724586
references.citation: Cancer Res. 2008 Jul 15;68(14):5733-42
references.pmid: 18632626
references.citation: Hum Mutat. 2007 Jan;28(1):1-12
references.pmid: 16983642
references.citation: J Cell Sci. 2009 Nov 15;122(Pt 22):4141-9
references.pmid: 19910496
references.citation: Science. 2014 Jan 3;343(6166):84-87
references.pmid: 24336571
references.citation: J Biol Chem. 1998 Aug 21;273(34):21893-900
references.pmid: 9705328
references.citation: J Cell Sci. 2001 May;114(Pt 10):1901-12
references.pmid: 11329377
references.citation: J Neurosci Res. 1998 Feb 1;51(3):403-15
references.pmid: 9486775
references.citation: Cell. 2006 May 5;125(3):535-48
references.pmid: 16678097
references.citation: J Biol Chem. 1994 Jun 3;269(22):15577-82
references.pmid: 8195203
references.citation: Cancer Cell. 2014 Jul 14;26(1):48-60
references.pmid: 25026211
references.citation: J Biol Chem. 1999 Nov 26;274(48):34438-42
references.pmid: 10567424
references.citation: PLoS Biol. 2010 Jul 13;8(7):e1000422
references.pmid: 20644714
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6
references.pmid: 20080598
references.citation: J Biol Chem. 2011 Feb 11;286(6):4364-70
references.pmid: 21187284
references.citation: J Cell Biol. 1998 Jun 29;141(7):1589-99
references.pmid: 9647651
references.citation: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8248-53
references.pmid: 20404163
references.citation: Nat Rev Drug Discov. 2014 Jan;13(1):63-79
references.pmid: 24336504
references.citation: Oncogene. 2014 Oct 9;33(41):4893-903
references.pmid: 24166499
references.citation: Oncogene. 2012 Mar 1;31(9):1189-95
references.pmid: 21785462
references.citation: Oncogene. 2013 Feb 28;32(9):1135-43
references.pmid: 22525268
references.citation: Oncogene. 2004 Nov 4;23(52):8447-54
references.pmid: 15378014
references.citation: Genes Dev. 2005 Oct 1;19(19):2265-77
references.pmid: 16204178
references.citation: J Biol Chem. 2010 Nov 26;285(48):37333-41
references.pmid: 20870715
references.citation: Sci Signal. 2013 Sep 03;6(291):ra77
references.pmid: 24003254
references.citation: J Neurosci Res. 1996 Dec 01;46(5):595-605
references.pmid: 8951671
references.citation: Cancer Genet Cytogenet. 1995 Oct 1;84(1):24-6
references.pmid: 7497438
references.citation: J Cell Biol. 1994 Jul;126(2):391-401
references.pmid: 7518464
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1437-42
references.pmid: 20080689
references.citation: EMBO J. 2012 Feb 15;31(4):945-58
references.pmid: 22157821
references.citation: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7311-6
references.pmid: 20368450
references.citation: Cell. 1999 Jan 22;96(2):235-44
references.pmid: 9988218
references.citation: J Biol Chem. 1998 Mar 27;273(13):7757-64
references.pmid: 9516485
references.citation: Cell. 2000 Apr 28;101(3):259-70
references.pmid: 10847681
references.citation: Genes Chromosomes Cancer. 1999 Mar;24(3):238-42
references.pmid: 10451704
references.citation: Development. 2011 Mar;138(5):947-57
references.pmid: 21303848
references.citation: Mol Cell Biol. 2011 May;31(10):1983-96
references.pmid: 21402777
references.citation: J Biol Chem. 2002 Mar 22;277(12):10332-6
references.pmid: 11756419
references.citation: Nature. 1993 Jun 10;363(6429):515-21
references.pmid: 8379998
references.citation: Trends Cell Biol. 2009 May;19(5):198-206
references.pmid: 19345106
references.citation: J Neurosci Res. 1997 Jul 15;49(2):236-47
references.pmid: 9272646
references.citation: Cell Growth Differ. 1998 Apr;9(4):287-96
references.pmid: 9563848
references.citation: Retrovirology. 2012 Oct 23;9:87
references.pmid: 23092122
references.citation: J Mol Biol. 2007 Feb 2;365(5):1446-59
references.pmid: 17134719
references.citation: Oncogene. 1997 Nov 13;15(20):2505-9
references.pmid: 9395247
references.citation: J Neurosci Res. 2000 Nov 15;62(4):491-502
references.pmid: 11070492
references.citation: Cancer Cell. 2009 Nov 6;16(5):425-38
references.pmid: 19878874
references.citation: J Biol Chem. 2001 Mar 9;276(10):7621-9
references.pmid: 11106646
references.citation: Nature. 2006 Oct 5;443(7111):590-3
references.pmid: 16964240
references.citation: Genes Dev. 2007 Nov 1;21(21):2747-61
references.pmid: 17974916
references.citation: Gene. 2001 Jan 24;263(1-2):131-40
references.pmid: 11223251
references.citation: Nat Genet. 1994 Feb;6(2):185-92
references.pmid: 8162073
references.citation: Dev Cell. 2012 Apr 17;22(4):703-5
references.pmid: 22516197
references.citation: Cell. 1993 Nov 19;75(4):826
references.pmid: 8242753
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11778-83
references.pmid: 17609381
references.citation: Nature. 2014 Jan 9;505(7482):234-8
references.pmid: 24336198
references.citation: Mol Cell Biol. 2009 Aug;29(15):4235-49
references.pmid: 19451229
references.citation: Cell. 2011 Mar 4;144(5):782-95
references.pmid: 21376238
references.citation: Cancer Cell. 2011 Apr 12;19(4):527-40
references.pmid: 21481793
references.citation: Nat Med. 2012 Nov;18(11):1682-7
references.pmid: 22972397
references.citation: Mol Cell Biol. 2010 Jan;30(1):54-67
references.pmid: 19884346
references.citation: Cancer Res. 2014 Jan 1;74(1):353-62
references.pmid: 24282279
references.citation: Nature. 2006 Aug 3;442(7102):576-9
references.pmid: 16885985
references.citation: Mol Cell Biol. 2012 Feb;32(4):783-96
references.pmid: 22184063
references.citation: Genes Dev. 2003 May 1;17(9):1090-100
references.pmid: 12695331
references.citation: Cancer Res. 2008 Jul 1;68(13):5236-45
references.pmid: 18593924
references.citation: Nat Genet. 2011 Jun 05;43(7):668-72
references.pmid: 21642991
references.citation: Nature. 2011 May 25;474(7353):654-7
references.pmid: 21613998
references.citation: J Cell Sci. 1997 Sep;110 ( Pt 18):2249-60
references.pmid: 9378774
references.citation: Dev Cell. 2010 Nov 16;19(5):727-39
references.pmid: 21074722
references.citation: Dev Cell. 2010 Feb 16;18(2):288-99
references.pmid: 20159598
references.citation: Nat Commun. 2013;4:2976
references.pmid: 24356468
references.citation: Blood. 2009 Jan 1;113(1):244-53
references.pmid: 18824598
references.citation: Curr Biol. 2010 Jul 13;20(13):R574-82
references.pmid: 20619814
references.citation: Genes Dev. 2011 Jan 1;25(1):51-63
references.pmid: 21205866
references.citation: Cell. 2013 Sep 12;154(6):1194-205
references.pmid: 24034244
references.citation: J Cell Biol. 1996 May;133(4):843-52
references.pmid: 8666669
references.citation: Cell Cycle. 2007 Jan 15;6(2):182-8
references.pmid: 17314515
references.citation: Cell. 2010 Feb 19;140(4):477-90
references.pmid: 20178741
references.citation: Development. 2012 Jun;139(11):1895-902
references.pmid: 22569552
references.citation: Cancer Res. 2009 May 1;69(9):4043-51
references.pmid: 19351837
references.citation: Nat Cell Biol. 2011 Aug 01;13(8):877-83
references.pmid: 21808241
references.citation: Mol Cell. 2003 Oct;12(4):841-9
references.pmid: 14580336
references.citation: J Biol Chem. 2012 Apr 6;287(15):12550-8
references.pmid: 22362772
references.citation: Nat Cell Biol. 2007 Oct;9(10):1199-207
references.pmid: 17891137
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18200-5
references.pmid: 15598747
references.citation: Mol Biol Cell. 1995 Aug;6(8):1061-75
references.pmid: 7579708
references.citation: Nat Struct Mol Biol. 2010 Jan;17(1):105-11
references.pmid: 19966799
references.citation: Cancer Res. 2004 Apr 15;64(8):2717-24
references.pmid: 15087385
references.citation: Nature. 2011 Jun 29;474(7353):658-61
references.pmid: 21720370
references.citation: Oncogene. 2006 Sep 28;25(44):5960-8
references.pmid: 16652148
references.citation: J Virol. 2002 Nov;76(22):11379-86
references.pmid: 12388698
references.citation: J Cell Biol. 2005 Oct 24;171(2):361-71
references.pmid: 16247032
references.citation: Genes Dev. 2001 Apr 15;15(8):968-80
references.pmid: 11316791
references.citation: Oncogene. 2002 Sep 5;21(39):5990-7
references.pmid: 12203111
references.citation: Nat Genet. 2008 Aug;40(8):1010-5
references.pmid: 18604206
references.citation: J Biol Chem. 2002 Mar 22;277(12):10394-9
references.pmid: 11782491
references.citation: Oncogene. 2008 May 22;27(23):3233-43
references.pmid: 18071304
references.citation: Nat Rev Mol Cell Biol. 2005 Jan;6(1):9-20
references.pmid: 15688063
references.citation: Genes Dev. 2013 Nov 15;27(22):2473-88
references.pmid: 24240237
references.citation: J Biol Chem. 2004 Apr 30;279(18):18559-66
references.pmid: 14981079
references.citation: Oncogene. 2005 Feb 10;24(7):1150-8
references.pmid: 15580288
references.citation: Cell Host Microbe. 2012 Feb 16;11(2):194-204
references.pmid: 22284954
references.citation: J Biol Chem. 2011 Mar 4;286(9):7018-26
references.pmid: 21224387
references.citation: Sci Signal. 2011 May 24;4(174):ra33
references.pmid: 21610251
references.citation: Mol Cell Biol. 2009 Aug;29(15):4250-61
references.pmid: 19451225
references.citation: Nature. 2010 Jan 21;463(7279):360-3
references.pmid: 20054297
references.citation: Curr Opin Cell Biol. 2012 Oct;24(5):685-94
references.pmid: 22835462
references.citation: Mol Biol Cell. 2011 Oct;22(19):3725-33
references.pmid: 21832154
references.citation: Dev Cell. 2010 Jul 20;19(1):27-38
references.pmid: 20643348
references.citation: Oncogene. 2014 Mar 6;33(10):1218-28
references.pmid: 23563179
references.citation: J Biol Chem. 1998 Jan 16;273(3):1273-6
references.pmid: 9430655
references.citation: Science. 2013 Dec 20;342(6165):1518-21
references.pmid: 24357321