CSL-Associated Corepressor and Coactivator Complexes

  • Franz OswaldEmail author
  • Rhett A. KovallEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1066)


The highly conserved Notch signal transduction pathway orchestrates fundamental cellular processes including, differentiation, proliferation, and apoptosis during embryonic development and in the adult organism. Dysregulated Notch signaling underlies the etiology of a variety of human diseases, such as certain types of cancers, developmental disorders and cardiovascular disease. Ligand binding induces proteolytic cleavage of the Notch receptor and nuclear translocation of the Notch intracellular domain (NICD), which forms a ternary complex with the transcription factor CSL and the coactivator MAML to upregulate transcription of Notch target genes. The DNA-binding protein CSL is the centrepiece of transcriptional regulation in the Notch pathway, acting as a molecular hub for interactions with either corepressors or coactivators to repress or activate, respectively, transcription. Here we review previous structure-function studies of CSL-associated coregulator complexes and discuss the molecular insights gleaned from this research. We discuss the functional consequences of both activating and repressing binding partners using the same interaction platforms on CSL. We also emphasize that although there has been a significant uptick in structural information over the past decade, it is still under debate how the molecular switch from repression to activation mediated by CSL occurs at Notch target genes and whether it will be possible to manipulate these transcription complexes therapeutically in the future.


Notch CSL Structure analysis RAM domain Coactivator complex Corepressor complex DNA-binding Transcription 



C-promoter Binding Factor 1


abnormal cell LINeage-12 (Lin-12) And abnormal Germ line proliferation phenotype-1 (Glp-1)


Recombination Signal-Binding Protein for immunoglobin kappa J region


Suppressor of Hairless


C-Adenosine Mono Phosphate Responsive Element (cAMP-RE)-Binding protein (CREB)-Binding Protein; KAT3A


E1A Binding Protein P300, KAT3B


P300/CBP-Associated Factor; KAT2B


General Control Of AmiNo Acid Synthesis Protein 5-Like 2; KAT2A


Cyclin-Dependent Kinase 8


S-Phase Kinase Associated Protein1/Cullin/F-Box Protein


Suppressor and/or Enhancer of abnormal cell LINeage-12 (Lin-12)-10


F-Box and WD Repeat Domain containing 7




Coactivator-Associated Arginine Methyltransferase1


Protein Arginine N-MethylTransferase 4


C-Terminal Binding Protein


CTBP Interacting Protein


Four and a Half LIM domains 1


Nuclear Receptor CoRepressor


Silencing Mediator For Retinoid And Thyroid Hormone Receptors


SMRT/HDAC1-Associated Repressor Protein


SPlit ENds family transcriptional repressor


Little Imaginal Disks


Lysine(K) Demethylase 5A


Corepressor Interacting with RBPJ


Sloan-KetterIng-retroviral oncogene (SKI) -Interacting Protein


Lethal(3)Malignant Brain Tumor-Like Protein 3


RBPJ Interacting and Tubulin Associated 1


Epstein-Barr Virus Nuclear Antigen 2


Nuclear Factor of Activated T-cells


Nuclear Factor κB1


Protein O-Fucosyltransferase 1





We want to thank Bernd Baumann for critical reading of the manuscript. Research in the F.O. laboratory is supported by the DFG (SFB1074/A3) and the BMBF (Federal Ministry of Education and Research, research nucleus SyStAR). Research in the R.A.K. laboratory is supported by the NIH (CA178974), NSF (MCB-1715822), and the Bankhead-Coley Cancer Research Program.


  1. Arnett KL, Hass M, McArthur DG, Ilagan MX, Aster JC, Kopan R, Blacklow SC (2010) Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. Nat Struct Mol Biol 17(11):1312–1317. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284(5415):770–776 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bailey AM, Posakony JW (1995) Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9(21):2609–2622 CrossRefPubMedGoogle Scholar
  4. Barolo S, Stone T, Bang AG, Posakony JW (2002) Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. Genes Dev 16(15):1964–1976. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bertagna A, Toptygin D, Brand L, Barrick D (2008) The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder. Biochem Soc Trans 36(Pt 2):157–166. CrossRefPubMedGoogle Scholar
  6. Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66(10):1631–1646 CrossRefPubMedGoogle Scholar
  7. Bozkulak EC, Weinmaster G (2009) Selective use of ADAM10 and ADAM17 in activation of Notch1 signaling. Mol Cell Biol 29(21):5679–5695. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7(9):678–689. CrossRefPubMedGoogle Scholar
  9. Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol 17(11):722–735. CrossRefPubMedGoogle Scholar
  10. Brockmann B, Mastel H, Oswald F, Maier D (2014) Analysis of the interaction between human RITA and Drosophila Suppressor of Hairless. Hereditas 151(6):209–219. CrossRefPubMedGoogle Scholar
  11. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israel A (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 5(2):207–216 CrossRefPubMedGoogle Scholar
  12. Bruckner K, Perez L, Clausen H, Cohen S (2000) Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406(6794):411–415. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Castel D, Mourikis P, Bartels SJ, Brinkman AB, Tajbakhsh S, Stunnenberg HG (2013) Dynamic binding of RBPJ is determined by Notch signaling status. Genes Dev 27(9):1059–1071. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Choi SH, Wales TE, Nam Y, O'Donovan DJ, Sliz P, Engen JR, Blacklow SC (2012) Conformational locking upon cooperative assembly of notch transcription complexes. Structure 20(2):340–349. CrossRefPubMedPubMedCentralGoogle Scholar
  15. Collins KJ, Yuan Z, Kovall RA (2014) Structure and function of the CSL-KyoT2 corepressor complex: a negative regulator of Notch signaling. Structure 22(1):70–81. CrossRefPubMedGoogle Scholar
  16. Contreras AN, Yuan Z, Kovall RA (2015) Thermodynamic binding analysis of Notch transcription complexes from Drosophila melanogaster. Protein Sci Publ Protein Soc 24(5):812–822. CrossRefGoogle Scholar
  17. Del Bianco C, Aster JC, Blacklow SC (2008) Mutational and energetic studies of Notch 1 transcription complexes. J Mol Biol 376(1):131–140 CrossRefPubMedGoogle Scholar
  18. Del Bianco C, Vedenko A, Choi SH, Berger MF, Shokri L, Bulyk ML, Blacklow SC (2010) Notch and MAML-1 complexation do not detectably alter the dna binding specificity of the transcription factor CSL. PLoS One 5(11):e15034. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Dou S, Zeng X, Cortes P, Erdjument-Bromage H, Tempst P, Honjo T, Vales LD (1994) The recombination signal sequence-binding protein RBP-2N functions as a transcriptional repressor. Mol Cell Biol 14(5):3310–3319 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Friedmann DR, Kovall RA (2010) Thermodynamic and structural insights into CSL-DNA complexes. Protein Sci Publ Protein Soc 19(1):34–46. CrossRefGoogle Scholar
  21. Friedmann DR, Wilson JJ, Kovall RA (2008) RAM-induced allostery facilitates assembly of a notch pathway active transcription complex. J Biol Chem 283(21):14781–14791. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Fryer CJ, White JB, Jones KA (2004) Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16(4):509–520. CrossRefPubMedGoogle Scholar
  23. Fuchs KP, Bommer G, Dumont E, Christoph B, Vidal M, Kremmer E, Kempkes B (2001) Mutational analysis of the J recombination signal sequence binding protein (RBPJ)/ Epstein-Barr virus nuclear antigen 2 (EBNA2) and RBP-J/Notch interaction. Eur J Biochem 268(17):4639–4646 CrossRefPubMedGoogle Scholar
  24. Gordon WR, Zimmerman B, He L, Miles LJ, Huang J, Tiyanont K, McArthur DG, Aster JC, Perrimon N, Loparo JJ, Blacklow SC (2015) Mechanical Allostery: evidence for a force requirement in the proteolytic activation of Notch. Dev Cell 33(6):729–736. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Guarani V, Deflorian G, Franco CA, Kruger M, Phng LK, Bentley K, Toussaint L, Dequiedt F, Mostoslavsky R, Schmidt MH, Zimmermann B, Brandes RP, Mione M, Westphal CH, Braun T, Zeiher AM, Gerhardt H, Dimmeler S, Potente M (2011) Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature 473(7346):234–238. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hass MR, Liow HH, Chen X, Sharma A, Inoue YU, Inoue T, Reeb A, Martens A, Fulbright M, Raju S, Stevens M, Boyle S, Park JS, Weirauch MT, Brent MR, Kopan R (2016) SpDamID: marking DNA bound by protein complexes identifies Notch-dimer responsive enhancers. Mol Cell 64(1):213. CrossRefPubMedGoogle Scholar
  27. Hein K, Mittler G, Cizelsky W, Kuhl M, Ferrante F, Liefke R, Berger IM, Just S, Strang JE, Kestler HA, Oswald F, Borggrefe T (2015) Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response. Sci Signal 8(369):ra30. CrossRefPubMedGoogle Scholar
  28. Hsieh JJ, Hayward SD (1995) Masking of the CBF1/RBPJ kappa transcriptional repression domain by Epstein-Barr virus EBNA2. Science 268(5210):560–563 CrossRefPubMedGoogle Scholar
  29. Hsieh JJ, Zhou S, Chen L, Young DB, Hayward SD (1999) CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc Natl Acad Sci U S A 96(1):23–28 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hu B, Castillo E, Harewood L, Ostano P, Reymond A, Dummer R, Raffoul W, Hoetzenecker W, Hofbauer GF, Dotto GP (2012) Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell 149(6):1207–1220. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Johnson SE, Ilagan MX, Kopan R, Barrick D (2010) Thermodynamic analysis of the CSL x Notch interaction: distribution of binding energy of the Notch RAM region to the CSL beta-trefoil domain and the mode of competition with the viral transactivator EBNA2. J Biol Chem 285(9):6681–6692. CrossRefPubMedGoogle Scholar
  32. Kadam S, Emerson BM (2003) Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes. Mol Cell 11(2):377–389 CrossRefPubMedGoogle Scholar
  33. Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T (1998) A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev 12(15):2269–2277 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137(2):216–233. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kovall RA, Blacklow SC (2010) Mechanistic insights into Notch receptor signaling from structural and biochemical studies. Curr Top Dev Biol 92:31–71. CrossRefPubMedGoogle Scholar
  36. Kovall RA, Hendrickson WA (2004) Crystal structure of the nuclear effector of Notch signaling, CSL, bound to DNA. EMBO J 23(17):3441–3451. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Kovall RA, Gebelein B, Sprinzak D, Kopan R (2017) The canonical notch signaling pathway: structural and biochemical insights into shape, sugar, and force. Dev Cell 41(3):228–241. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Krejci A, Bray S (2007) Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers. Genes Dev 21(11):1322–1327 Scholar
  39. Kulic I, Robertson G, Chang L, Baker JH, Lockwood WW, Mok W, Fuller M, Fournier M, Wong N, Chou V, Robinson MD, Chun HJ, Gilks B, Kempkes B, Thomson TA, Hirst M, Minchinton AI, Lam WL, Jones S, Marra M, Karsan A (2015) Loss of the Notch effector RBPJ promotes tumorigenesis. J Exp Med 212(1):37–52. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kuroda K, Han H, Tani S, Tanigaki K, Tun T, Furukawa T, Taniguchi Y, Kurooka H, Hamada Y, Toyokuni S, Honjo T (2003) Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18(2):301–312 CrossRefPubMedGoogle Scholar
  41. Kurooka H, Honjo T (2000) Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. J Biol Chem 275(22):17211–17220. CrossRefPubMedGoogle Scholar
  42. Liefke R, Oswald F, Alvarado C, Ferres-Marco D, Mittler G, Rodriguez P, Dominguez M, Borggrefe T (2010) Histone demethylase KDM5A is an integral part of the core Notch- RBP-J repressor complex. Genes Dev 24(6):590–601 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israel A (1998) The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci U S A 95(14):8108–8112 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Lubman OY, Ilagan MX, Kopan R, Barrick D (2007) Quantitative dissection of the Notch:CSL interaction: insights into the Notch-mediated transcriptional switch. J Mol Biol 365(3):577–589. CrossRefPubMedGoogle Scholar
  45. Maier D (2006) Hairless: the ignored antagonist of the Notch signalling pathway. Hereditas 143(2006):212–221. CrossRefPubMedGoogle Scholar
  46. Maier D, Kurth P, Schulz A, Russell A, Yuan Z, Gruber K, Kovall RA, Preiss A (2011) Structural and functional analysis of the repressor complex in the Notch signaling pathway of Drosophila melanogaster. Mol Biol Cell 22(17):3242–3252 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Meng X, Brodsky MH, Wolfe SA (2005) A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors. Nat Biotechnol 23(8):988–994 Scholar
  48. Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF (2000) Fringe is a glycosyltransferase that modifies Notch. Nature 406(6794):369–375. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Morel V, Lecourtois M, Massiani O, Maier D, Preiss A, Schweisguth F (2001) Transcriptional repression by suppressor of hairless involves the binding of a hairless-dCtBP complex in Drosophila. Curr Biol 11(10):789–792 CrossRefPubMedGoogle Scholar
  50. Morgan TH (1917) The theory of the gene. Am Nat 51:513–544 CrossRefGoogle Scholar
  51. Moshkin YM, Kan TW, Goodfellow H, Bezstarosti K, Maeda RK, Pilyugin M, Karch F, Bray SJ, Demmers JA, Verrijzer CP (2009) Histone chaperones ASF1 and NAP1 differentially modulate removal of active histone marks by LID-RPD3 complexes during NOTCH silencing. Mol Cell 35(6):782–793. CrossRefPubMedGoogle Scholar
  52. Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, Pan DJ, Ray WJ, Kopan R (2000) A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5(2):197–206 Scholar
  53. Nagel AC, Krejci A, Tenin G, Bravo-Patino A, Bray S, Maier D, Preiss A (2005) Hairless-mediated repression of notch target genes requires the combined activity of Groucho and CtBP corepressors. Mol Cell Biol 25(23):10433–10441. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Nam Y, Weng AP, Aster JC, Blacklow SC (2003) Structural requirements for assembly of the CSL.intracellular Notch1. Mastermind-like 1 transcriptional activation complex. J Biol Chem 278(23):21232–21239. CrossRefPubMedGoogle Scholar
  55. Nam Y, Sliz P, Song L, Aster JC, Blacklow SC (2006) Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124(5):973–983. CrossRefPubMedGoogle Scholar
  56. Nam Y, Sliz P, Pear WS, Aster JC, Blacklow SC (2007) Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proc Natl Acad Sci U S A 104(7):2103–2108. doi:0611092104 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Neves A, English K, Priess JR (2007) Notch-GATA synergy promotes endoderm-specific expression of ref-1 in C. elegans. Development 134(24):4459–4468 CrossRefPubMedGoogle Scholar
  58. Okajima T, Xu A, Irvine KD (2003) Modulation of notch-ligand binding by protein O-fucosyltransferase 1 and fringe. J Biol Chem 278(43):42340–42345. CrossRefPubMedGoogle Scholar
  59. Olave I, Reinberg D, Vales LD (1998) The mammalian transcriptional repressor RBP (CBF1) targets TFIID and TFIIA to prevent activated transcription. Genes Dev 12(11):1621–1637 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Oswald F, Tauber B, Dobner T, Bourteele S, Kostezka U, Adler G, Liptay S, Schmid RM (2001) p300 acts as a transcriptional coactivator for mammalian Notch-1. Mol Cell Biol 21(22):7761–7774. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K, Zechner U, Ludwig L, Wilda M, Hameister H, Knochel W, Liptay S, Schmid RM (2002) SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO J 21(20):5417–5426 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Oswald F, Winkler M, Cao Y, Astrahantseff K, Bourteele S, Knochel W, Borggrefe T (2005) RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes. Mol Cell Biol 25(23):10379–10390 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Oswald F, Rodriguez P, Giaimo BD, Antonello ZA, Mira L, Mittler G, Thiel VN, Collins KJ, Tabaja N, Cizelsky W, Rothe M, Kuhl SJ, Kuhl M, Ferrante F, Hein K, Kovall RA, Dominguez M, Borggrefe T (2016) A phospho-dependent mechanism involving NCoR and KMT2D controls a permissive chromatin state at Notch target genes. Nucleic Acids Res 44(10):4703–4720 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Prevorovsky M, Atkinson SR, Ptackova M, McLean JR, Gould K, Folk P, Puta F, Bahler J (2011) N-termini of fungal CSL transcription factors are disordered, enriched in regulatory motifs and inhibit DNA binding in fission yeast. PLoS One 6(8):e23650. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Qin H, Wang J, Liang Y, Taniguchi Y, Tanigaki K, Han H (2004) RING1 inhibits transactivation of RBP-J by Notch through interaction with LIM protein KyoT2. Nucleic Acids Res 32(4):1492–1501. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Qin H, Du D, Zhu Y, Li J, Feng L, Liang Y, Han H (2005) The PcG protein HPC2 inhibits RBP-J-mediated transcription by interacting with LIM protein KyoT2. FEBS Lett 579(5):1220–1226. CrossRefPubMedGoogle Scholar
  67. Rana NA, Haltiwanger RS (2011) Fringe benefits: functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors. Curr Opin Struct Biol 21(5):583–589. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Schroeter EH, Kisslinger JA, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393(6683):382–386. CrossRefPubMedGoogle Scholar
  69. Sherry KP, Johnson SE, Hatem CL, Majumdar A, Barrick D (2015) Effects of linker length and transient secondary structure elements in the intrinsically disordered notch RAM region on notch signaling. J Mol Biol 427(22):3587–3597. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Steinhauser K, Kloble P, Kreis NN, Ritter A, Friemel A, Roth S, Reichel JM, Michaelis J, Rieger MA, Louwen F, Oswald F, Yuan J (2016) Deficiency of RITA results in multiple mitotic defects by affecting microtubule dynamics. Oncogene.
  71. Struhl G, Adachi A (1998) Nuclear access and action of notch in vivo. Cell 93(4):649–660 CrossRefPubMedGoogle Scholar
  72. Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398(6727):522–525. CrossRefPubMedGoogle Scholar
  73. Surendran K, Boyle S, Barak H, Kim M, Stomberski C, McCright B, Kopan R (2010) The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage. Dev Biol 337(2):386–395. CrossRefPubMedGoogle Scholar
  74. Tabaja N, Yuan Z, Oswald F, Kovall RA (2017) Structure-function analysis of RBP-J-interacting and tubulin-associated (RITA) reveals regions critical for repression of Notch target genes. J Biol Chem 292(25):10549–10563. CrossRefPubMedPubMedCentralGoogle Scholar
  75. Takeuchi H, Haltiwanger RS (2010) Role of glycosylation of Notch in development. Semin Cell Dev Biol 21(6):638–645. CrossRefPubMedPubMedCentralGoogle Scholar
  76. Takeuchi H, Haltiwanger RS (2014) Significance of glycosylation in Notch signaling. Biochem Biophys Res Commun 453(2):235–242. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T, Furukawa T, Honjo T (1995) Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-J kappa/Su(H). Curr Biol 5(12):1416–1423 CrossRefPubMedGoogle Scholar
  78. Taniguchi Y, Furukawa T, Tun T, Han H, Honjo T (1998) LIM protein KyoT2 negatively regulates transcription by association with the RBP-J DNA-binding protein. Mol Cell Biol 18(1):644–654 CrossRefPubMedPubMedCentralGoogle Scholar
  79. Torella R, Li J, Kinrade E, Cerda-Moya G, Contreras AN, Foy R, Stojnic R, Glen RC, Kovall RA, Adryan B, Bray SJ (2014) A combination of computational and experimental approaches identifies DNA sequence constraints associated with target site binding specificity of the transcription factor CSL. Nucleic Acids Res 42(16):10550–10563. CrossRefPubMedPubMedCentralGoogle Scholar
  80. Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, Bessho Y, Kageyama R, Suda T, Nakayama KI (2004) Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J Biol Chem 279(10):9417–9423. CrossRefPubMedGoogle Scholar
  81. Tun T, Hamaguchi Y, Matsunami N, Furukawa T, Honjo T, Kawaichi M (1994) Recognition sequence of a highly conserved DNA binding protein RBP-J kappa. Nucleic Acids Res 22(6):965–971Google Scholar
  82. VanderWielen BD, Yuan Z, Friedmann DR, Kovall RA (2011) Transcriptional repression in the Notch pathway: thermodynamic characterization of CSL-MINT (Msx2-interacting nuclear target protein) complexes. J Biol Chem 286(17):14892–14902. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Wacker SA, Alvarado C, von Wichert G, Knippschild U, Wiedenmann J, Clauss K, Nienhaus GU, Hameister H, Baumann B, Borggrefe T, Knochel W, Oswald F (2011) RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J. EMBO J 30(1):43–56 CrossRefPubMedGoogle Scholar
  84. Wallberg AE, Pedersen K, Lendahl U, Roeder RG (2002) p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Mol Cell Biol 22(22):7812–7819 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, Aster JC (2003) Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 23(2):655–664 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (1985) Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43(3 Pt 2):567–581CrossRefPubMedGoogle Scholar
  87. Wilson JJ, Kovall RA (2006) Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell 124(5):985–996. CrossRefPubMedGoogle Scholar
  88. Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J (2001) SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol Cell Biol 21(21):7403–7415. CrossRefPubMedPubMedCentralGoogle Scholar
  89. Xu T, Park SS, Giaimo BD, Hall D, Ferrante F, Ho DM, Hori K, Anhezini L, Ertl I, Bartkuhn M, Zhang H, Milon E, Ha K, Conlon KP, Kuick R, Govindarajoo B, Zhang Y, Sun Y, Dou Y, Basrur V, Elenitoba-Johnson KS, Nesvizhskii AI, Ceron J, Lee CY, Borggrefe T, Kovall RA, Rual JF (2017) RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1. EMBO J 36(21):3232–3249. CrossRefPubMedPubMedCentralGoogle Scholar
  90. Yuan Z, Friedmann DR, VanderWielen BD, Collins KJ, Kovall RA (2012) Characterization of CSL (CBF-1, Su(H), Lag-1) mutants reveals differences in signaling mediated by Notch1 and Notch2. J Biol Chem 287(42):34904–34916. doi:M112.403287 [pii]. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Yuan Z, Praxenthaler H, Tabaja N, Torella R, Preiss A, Maier D, Kovall RA (2016) Structure and function of the Su(H)-Hairless repressor complex, the major antagonist of notch signaling in Drosophila melanogaster. PLoS Biol 14(7):e1002509. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Zhou S, Hayward SD (2001) Nuclear localization of CBF1 is regulated by interactions with the SMRT corepressor complex. Mol Cell Biol 21(18):6222–6232 CrossRefPubMedPubMedCentralGoogle Scholar
  93. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD (2000) SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC to facilitate NotchIC function. Mol Cell Biol 20(7):2400–2410 Scholar
  94. Zweifel ME, Leahy DJ, Hughson FM, Barrick D (2003) Structure and stability of the ankyrin domain of the Drosophila Notch receptor. Protein Sci Publ Protein Soc 12(11):2622–2632. CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine IUniversity of UlmUlmGermany
  2. 2.Department of Molecular Genetics, Biochemistry and MicrobiologyUniversity of Cincinnati College of MedicineCincinnatiUSA

Personalised recommendations