title: cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes.
abstract: Actin cytoskeletal damage induces inactivation of the oncoprotein YAP (Yes-associated protein). It is known that the serine/threonine kinase LATS (large tumour suppressor) inactivates YAP by phosphorylating its Ser127 and Ser381 residues. However, the events downstream of actin cytoskeletal changes that are involved in the regulation of the LATS-YAP pathway and the mechanism by which LATS differentially phosphorylates YAP on Ser127 and Ser381 in vivo have remained elusive. Here, we show that cyclic AMP (cAMP)-dependent protein kinase (PKA) phosphorylates LATS and thereby enhances its activity sufficiently to phosphorylate YAP on Ser381. We also found that PKA activity is involved in all contexts previously reported to trigger the LATS-YAP pathway, including actin cytoskeletal damage, G-protein-coupled receptor activation, and engagement of the Hippo pathway. Inhibition of PKA and overexpression of YAP cooperate to transform normal cells and amplify neural progenitor pools in developing chick embryos. We also implicate neurofibromin 2 as an AKAP (A-kinase-anchoring protein) scaffold protein that facilitates the function of the cAMP/PKA-LATS-YAP pathway. Our study thus incorporates PKA as novel component of the Hippo pathway.
authors: National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology KAIST, Daejeon 305-701, Republic of Korea.
authors: Minchul
authors: M
authors: Kim
authors: Miju
authors: M
authors: Kim
authors: Seunghee
authors: S
authors: Lee
authors: Shinji
authors: S
authors: Kuninaka
authors: Hideyuki
authors: H
authors: Saya
authors: Ho
authors: H
authors: Lee
authors: Sookyung
authors: S
authors: Lee
authors: Dae-Sik
authors: DS
authors: Lim
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D002642:Chick Embryo; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D000090683:Hippo Signaling Pathway; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D025581:Neurofibromin 2 / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012694:Serine; D015398:Signal Transduction / Q000502:physiology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D025581:Neurofibromin 2; D015513:Oncogene Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D012694:Serine; D000242:Cyclic AMP; C490501:Lats1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases
references: Development. 2011 Sep;138(18):3907-14
references: 21831922
references: Nat Cell Biol. 2000 Sep;2(9):593-600
references: 10980699
references: EMBO J. 2011 May 10;30(12):2325-35
references: 21556047
references: Nature. 1998 Dec 3;396(6710):474-7
references: 9853756
references: Mol Biol Cell. 2011 Oct;22(19):3725-33
references: 21832154
references: Cancer Res. 2005 Sep 1;65(17):7561-7
references: 16140918
references: Nat Cell Biol. 2006 Jan;8(1):27-36
references: 16341207
references: Neuron. 2009 Mar 26;61(6):839-51
references: 19323994
references: Oncogene. 2005 Jun 16;24(26):4232-42
references: 15824737
references: Int J Cell Biol. 2012;2012:306879
references: 22505926
references: Nature. 2012 Oct 25;490(7421):547-51
references: 23023132
references: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13438-43
references: 17679696
references: Nat Rev Cancer. 2007 Mar;7(3):182-91
references: 17318211
references: Oncogene. 2005 Mar 17;24(12):2076-86
references: 15688006
references: Hum Mol Genet. 2003 Apr 1;12(7):791-801
references: 12651874
references: Cancer Res. 2001 Sep 15;61(18):6629-34
references: 11559525
references: Nat Rev Mol Cell Biol. 2004 Dec;5(12):959-70
references: 15573134
references: Cell Oncol. 2005;27(3):191-8
references: 16037640
references: Dev Cell. 2010 Oct 19;19(4):491-505
references: 20951342
references: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1312-20
references: 22042863
references: Cell. 2012 Aug 17;150(4):780-91
references: 22863277
references: Cancer Res. 2009 Feb 1;69(3):1089-98
references: 19141641
references: J Biol Chem. 2003 Oct 17;278(42):41167-72
references: 12896975
references: EMBO J. 2001 Apr 2;20(7):1651-62
references: 11285229
references: J Biol Chem. 1990 Apr 25;265(12):6569-75
references: 1691172
references: J Biol Chem. 1997 Sep 19;272(38):23637-44
references: 9295304
references: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6
references: 20080598
references: J Biol Chem. 2011 Feb 11;286(6):4364-70
references: 21187284
references: Proc Natl Acad Sci U S A. 2010 May 4;107(18):8248-53
references: 20404163
references: Development. 2011 Jan;138(1):9-22
references: 21138973
references: Curr Opin Cell Biol. 2011 Aug;23(4):377-82
references: 21592758
references: Development. 2011 Jun;138(11):2337-46
references: 21525075
references: Nature. 2011 Jun 08;474(7350):179-83
references: 21654799
references: Genes Dev. 2010 May;24(9):862-74
references: 20439427
references: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10
references: 16894141
references: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1437-42
references: 20080689
references: J Biol Chem. 1998 Mar 27;273(13):7757-64
references: 9516485
references: Mol Pharmacol. 1983 Sep;24(2):195-202
references: 6310361
references: J Neurosci. 2001 Aug 15;21(16):6000-7
references: 11487623
references: Lab Invest. 1996 Jan;74(1):108-19
references: 8569172
references: Neoplasia. 2005 Jun;7(6):556-62
references: 16036106
references: Cell. 2007 Sep 21;130(6):1120-33
references: 17889654
references: Genes Dev. 2010 Nov 1;24(21):2383-8
references: 21041407
references: Cancer Cell. 2009 Nov 6;16(5):425-38
references: 19878874
references: Cancer Res. 2002 Sep 1;62(17):4860-6
references: 12208731
references: Genes Dev. 2010 Jan 1;24(1):72-85
references: 20048001
references: Genes Dev. 2008 Dec 1;22(23):3320-34
references: 19015275
references: EMBO J. 1997 Jan 2;16(1):35-43
references: 9009265
references: J Biol Chem. 2006 Jul 28;281(30):21535-21545
references: 16728392
references: Biochem Biophys Res Commun. 2006 Jun 23;345(1):50-8
references: 16674920
references: Nat Neurosci. 2001 Feb;4(2):123-4
references: 11175869
references: Genes Dev. 2007 Nov 1;21(21):2747-61
references: 17974916
references: Cancer Lett. 2008 Dec 18;272(2):177-85
references: 18579285
references: Science. 2002 May 31;296(5573):1648-9
references: 12040181
references: Nat Rev Mol Cell Biol. 2012 Sep;13(9):591-600
references: 22895435
references: Cell. 2002 Jul 26;110(2):237-49
references: 12150931
references: Mol Cell. 2006 Nov 3;24(3):383-95
references: 17081989
references: Cancer Cell. 2011 Apr 12;19(4):527-40
references: 21481793
references: Proc Natl Acad Sci U S A. 1992 May 15;89(10):4726-30
references: 1584809
references: Dev Cell. 2010 Feb 16;18(2):309-16
references: 20159600
references: J Biol Chem. 1991 Aug 5;266(22):14188-92
references: 1860836
references: Trends Biochem Sci. 2010 Nov;35(11):627-33
references: 20598891
references: Dev Cell. 2010 Feb 16;18(2):288-99
references: 20159598
references: Curr Biol. 2010 Jul 13;20(13):R574-82
references: 20619814
references: Genes Dev. 2011 Jan 1;25(1):51-63
references: 21205866
references: Genes Dev. 2012 Jan 1;26(1):54-68
references: 22215811
references: Cell. 2005 Aug 12;122(3):421-34
references: 16096061
references: Oncogene. 2012 Jan 12;31(2):238-50
references: 21666719
references: Curr Biol. 2010 Sep 14;20(17):1580-7
references: 20727758
references: Dev Cell. 2010 Feb 16;18(2):300-8
references: 20159599
references: J Biol Chem. 2000 May 5;275(18):13812-8
references: 10788503
references: Nat Cell Biol. 2009 Dec;11(12):1444-50
references: 19935651
references: Neuroreport. 2005 Aug 22;16(12):1357-61
references: 16056139
references: EMBO J. 2008 Apr 23;27(8):1231-42
references: 18369314
references: Dev Biol. 2012 Jan 1;361(1):103-15
references: 22037235
references: Curr Biol. 2007 Dec 4;17(23):2054-60
references: 17980593
references: J Biol Chem. 2011 Mar 4;286(9):7018-26
references: 21224387
references: J Biol Chem. 1989 Jan 5;264(1):431-6
references: 2535842
references: J Biol Chem. 2011 Feb 18;286(7):5414-22
references: 21149450
references: J Biol Chem. 1987 Sep 25;262(27):13111-9
references: 2820963