title: Structural basis for autoactivation of human Mst2 kinase and its regulation by RASSF5.
abstract: The tumor-suppressive Hippo pathway controls tissue homeostasis through balancing cell proliferation and apoptosis. Activation of the kinases Mst1 and Mst2 (Mst1/2) is a key upstream event in this pathway and remains poorly understood. Mst1/2 and their critical regulators RASSFs contain Salvador/RASSF1A/Hippo (SARAH) domains that can homo- and heterodimerize. Here, we report the crystal structures of human Mst2 alone and bound to RASSF5. Mst2 undergoes activation through transautophosphorylation at its activation loop, which requires SARAH-mediated homodimerization. RASSF5 disrupts Mst2 homodimer and blocks Mst2 autoactivation. Binding of RASSF5 to already activated Mst2, however, does not inhibit its kinase activity. Thus, RASSF5 can act as an inhibitor or a potential positive regulator of Mst2, depending on whether it binds to Mst2 before or after activation-loop phosphorylation. We propose that these temporally sensitive functions of RASSFs enable the Hippo pathway to respond to and integrate diverse cellular signals.
authors: Department of Pharmacology, The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors: Lisheng
authors: L
authors: Ni
authors: Sheng
authors: S
authors: Li
authors: Jianzhong
authors: J
authors: Yu
authors: Jungki
authors: J
authors: Min
authors: Chad A
authors: CA
authors: Brautigam
authors: Diana R
authors: DR
authors: Tomchick
authors: Duojia
authors: D
authors: Pan
authors: Xuelian
authors: X
authors: Luo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D020134:Catalytic Domain; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D020559:Monomeric GTP-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C454042:RASSF5 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases
references: Sci Signal. 2009 Sep 29;2(90):ra59
references: 19797269
references: Semin Cell Dev Biol. 2012 Sep;23(7):770-84
references: 22898666
references: J Biol Chem. 2008 Feb 29;283(9):5496-509
references: 18158288
references: Semin Cell Dev Biol. 2012 Sep;23(7):827-33
references: 22609812
references: J Biol Chem. 2009 Apr 24;284(17):11001-5
references: 19091744
references: J Biomol NMR. 1995 Nov;6(3):277-93
references: 8520220
references: J Biol Chem. 1996 Aug 30;271(35):21049-53
references: 8702870
references: Genes Dev. 2007 Nov 1;21(21):2747-61
references: 17974916
references: Genes Dev. 2008 Jul 15;22(14):1962-71
references: 18579750
references: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references: 15572765
references: Cell. 2005 Aug 12;122(3):421-34
references: 16096061
references: Q Rev Biophys. 2000 May;33(2):161-97
references: 11131563
references: Anal Biochem. 2003 Sep 1;320(1):104-24
references: 12895474
references: Nat Rev Cancer. 2007 Mar;7(3):182-91
references: 17318211
references: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
references: 21460441
references: Oncogene. 2004 Apr 22;23(19):3426-33
references: 15007383
references: J Biomol NMR. 1994 Sep;4(5):603-14
references: 22911360
references: J Mol Biol. 1993 Jan 5;229(1):105-24
references: 7678431
references: Dev Cell. 2010 Oct 19;19(4):491-505
references: 20951342
references: Biochem J. 2004 Jul 15;381(Pt 2):453-62
references: 15109305
references: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W375-83
references: 17452350
references: Curr Biol. 2002 Feb 19;12(4):253-65
references: 11864565
references: J Mol Biol. 2006 Aug 11;361(2):312-26
references: 16837009
references: Development. 2011 Jan;138(1):9-22
references: 21138973
references: Methods Enzymol. 1997;276:307-26
references: 27754618
references: Genes Dev. 2010 May;24(9):862-74
references: 20439427
references: Curr Biol. 2007 Apr 17;17(8):700-5
references: 17379520
references: Cancer Res. 2005 Jan 1;65(1):92-8
references: 15665283
references: Biochim Biophys Acta. 2009 Dec;1796(2):114-28
references: 19344752
references: Cell. 2007 Sep 21;130(6):1120-33
references: 17889654
references: Genes Dev. 2010 Jan 1;24(1):72-85
references: 20048001
references: Protein Cell. 2010 Sep;1(9):811-9
references: 21203923
references: Biochem Soc Trans. 2012 Feb;40(1):124-8
references: 22260677
references: Proc Natl Acad Sci U S A. 2007 May 29;104(22):9236-41
references: 17517604
references: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references: 20124702
references: Dev Cell. 2010 Feb 16;18(2):288-99
references: 20159598
references: Mol Cell. 2007 Sep 21;27(6):962-75
references: 17889669
references: Semin Cell Dev Biol. 2012 Sep;23(7):785-93
references: 22659496
references: Curr Biol. 2006 Dec 19;16(24):2459-65
references: 17174922
references: Cancer Res. 2006 Mar 1;66(5):2562-9
references: 16510573
references: Dev Dyn. 2012 Jan;241(1):3-15
references: 22174083
references: Biochem Biophys Res Commun. 2010 Jan 1;391(1):969-73
references: 19962960
references: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references: 19461840
references: Oncogene. 2009 Aug 20;28(33):2988-98
references: 19525978
references: Curr Opin Cell Biol. 2009 Dec;21(6):837-43
references: 19846288
references: Nat Rev Cancer. 2013 Apr;13(4):246-57
references: 23467301
references: Methods. 2011 May;54(1):4-15
references: 21187153
references: J Biol Chem. 2012 Feb 17;287(8):5784-96
references: 22215676
references: Cell. 2006 Jan 27;124(2):267-73
references: 16439203