Notch Signaling in Pancreatic Morphogenesis and Pancreatic Cancer Pathogenesis

  • Gwen Lomberk
  • Raul Urrutia
Reference work entry


Notch signaling is becoming the focus of investigation in a large number of laboratories around the world due to its pleiotropic effect in regulating normal development and alterations in cancer. During the last decade, the scientific community studying this pathway has made significant contributions to our understanding of the cellular role of Notch signaling in regulating proliferation, differentiation, apoptosis, migration, branching morphogenesis, and angiogenesis. Similar to observations with other signaling cascades, such as TGBβ, besides its role in morphogenesis, Notch signaling becomes dysregulated in adult tissue and contributes to the development and maintenance of the cancer phenotype. Elegant studies in this field of research have lead to not only the better understanding of the molecules within the pathway, but as a consequence, rational design of drugs that can inhibit Notch signaling with promising results. The study of Notch signaling in the pancreas has dawned on solid ground and thus, we predict that in the next few years, a better understanding of the pathway at the mechanistic level, along with a strict testing of pharmacological antagonists, will advance the field of pancreatic cancer research in a significant manner.


Pancreatic Cancer Notch Signaling Notch Pathway Notch Receptor Notch Target Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Work in the author’s laboratory (R.U.) is supported by funding from the National Institutes of Health DK 52913 and Mayo Clinic Pancreatic SPORE (P50 CA102701).


  1. 1.
    Horowitz A, Simons M: Branching morphogenesis. Circ Res 2008;103:784–795.CrossRefPubMedGoogle Scholar
  2. 2.
    Ghosh B, Leach SD: Interactions between hairy/enhancer of split-related proteins and the pancreatic transcription factor Ptf1-p48 modulate function of the PTF1 transcriptional complex. Biochem J 2006;393:679–685.CrossRefPubMedGoogle Scholar
  3. 3.
    Leach S: Epithelial differentiation in pancreatic development and neoplasia: new niches for nestin and Notch. J Clin Gastroenterol 2005;39:S78–S82.CrossRefPubMedGoogle Scholar
  4. 4.
    Lomberk G, Fernandez-Zapico M, Urrutia R: When developmental signaling pathways go wrong and their impact on pancreatic cancer development. Curr Opin Gastroenterol 2005;21:555–560.CrossRefPubMedGoogle Scholar
  5. 5.
    Masui T, Long Q, Beres T, Magnuson M, MacDonald R: Early pancreatic development requires the vertebrate suppressor of hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev 2007;21:2629–2643.CrossRefPubMedGoogle Scholar
  6. 6.
    Murtaugh LC, Stanger BZ, Kwan KM, Melton DA: Notch signaling controls multiple steps of pancreatic differentiation. Proc Natl Acad Sci USA 2003;100:14920–14925.CrossRefPubMedGoogle Scholar
  7. 7.
    Nakhai H, Siveke J, Klein B, Mendoza-Torres L, Mazur P, Algul H, Radtke F, Strobl L, Zimber-Strobl U, Schmid R: Conditional ablation of Notch signaling in pancreatic development. Development 2008;135:2757–2765.CrossRefPubMedGoogle Scholar
  8. 8.
    McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB: NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am J Hum Gen 2006;79:169–173.CrossRefGoogle Scholar
  9. 9.
    Miele L, Golde T, Osborne B: Notch signaling in cancer. Curr Mol Med 2006;6:905–918.CrossRefPubMedGoogle Scholar
  10. 10.
    Miele L, Miao H, Nickoloff BJ: NOTCH signaling as a novel cancer therapeutic target. Curr Cancer Drug Targets 2006;6:313–323.CrossRefPubMedGoogle Scholar
  11. 11.
    Talora C, Campese AF, Bellavia D, Felli MP, Vacca A, Gulino A, Screpanti I: Notch signaling and diseases: an evolutionary journey from a simple beginning to complex outcomes. Biochim Biophys Acta 2008;1782:489–497.PubMedGoogle Scholar
  12. 12.
    Turnpenny P, Alman B, Cornier A, Giampietro P, Offiah A, Tassy O, Pourquié O, Kusumi K, Dunwoodie S: Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dyn 2007;236:1456–1474.CrossRefPubMedGoogle Scholar
  13. 13.
    Warthen D, Moore E, Kamath B, Morrissette J, Sanchez P, Piccoli D, Krantz I, Spinner N: Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat 2006;27:436–443.CrossRefPubMedGoogle Scholar
  14. 14.
    Watt FM, Estrach S, Ambler CA: Epidermal Notch signalling: differentiation, cancer and adhesion. Curr Opin Cell Biol 2008;20:171–179.CrossRefPubMedGoogle Scholar
  15. 15.
    Siveke T, ÄìMartellato CL, Lee M, Mazur P, Nakhai H, Radtke F, Schmid R: Notch signaling is required for exocrine regeneration after acute pancreatitis. Gastroenterology 2008;134:544–555.CrossRefPubMedGoogle Scholar
  16. 16.
    De La O J-P, Emerson LL, Goodman JL, Froebe SC, Illum BE, Curtis AB, Murtaugh LC: Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci USA 2008;105:18907–18912.CrossRefGoogle Scholar
  17. 17.
    Fleming RJ: Structural conservation of Notch receptors and ligands. Semin Cell Dev Biol 1998;9:599–607.CrossRefPubMedGoogle Scholar
  18. 18.
    Lomberk G, Urrutia R: Primers on molecular pathways – notch. Pancreatology 2008;8:103–104.CrossRefPubMedGoogle Scholar
  19. 19.
    Wilson A, Radtke F: Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett 2006;580:2860–2868.CrossRefPubMedGoogle Scholar
  20. 20.
    D'Souza B, Miyamoto A, Weinmaster G: The many facets of Notch ligands. Oncogene 2008;27:5148–5167.CrossRefPubMedGoogle Scholar
  21. 21.
    LaVoie MJ, Selkoe DJ: The Notch ligands, jagged and delta, are sequentially processed by {alpha}-secretase and presenilin/{gamma}-secretase and release signaling fragments. J Biol Chem 2003;278:34427–34437.CrossRefPubMedGoogle Scholar
  22. 22.
    Gonczy P: Mechanisms of asymmetric cell division: flies and worms pave the way. Nat Rev Mol Cell Biol 2008;9:355–366.CrossRefPubMedGoogle Scholar
  23. 23.
    Gordon WR, Arnett KL, Blacklow SC: The molecular logic of Notch signaling – a structural and biochemical perspective. J Cell Sci 2008;121:3109–3119.CrossRefPubMedGoogle Scholar
  24. 24.
    Parks AL, Stout JR, Shepard SB, Klueg KM, Dos Santos AA, Parody TR, Vaskova M, Muskavitch MAT: Structure-function analysis of delta trafficking, receptor binding and signaling in drosophila. Genetics 2006;174:1947–1961.CrossRefPubMedGoogle Scholar
  25. 25.
    Shimizu K, Chiba S, Kumano K, Hosoya N, Takahashi T, Kanda Y, Hamada Y, Yazaki Y, Hirai H: Mouse jagged1 physically interacts with Notch2 and other Notch receptors. Assessment by quantitative methods. J Biol Chem 1999;274:32961–32969.CrossRefPubMedGoogle Scholar
  26. 26.
    Fiuza U-M, Arias AM: Cell and molecular biology of Notch. J Endocrinol 2007;194:459–474.CrossRefPubMedGoogle Scholar
  27. 27.
    Pintar A, De Biasio A, Popovic M, Ivanova N, Pongor S: The intracellular region of Notch ligands: does the tail make the difference? Biol Direct 2007;2:19.CrossRefPubMedGoogle Scholar
  28. 28.
    Wheeler SR, Stagg SB, Crews ST: Multiple Notch signaling events control drosophila CNS midline neurogenesis, gliogenesis and neuronal identity. Development 2008;135:3071–3079.CrossRefPubMedGoogle Scholar
  29. 29.
    Nichols J, Miyamoto A, Weinmaster G: Notch signaling: constantly on the move. Traffic 2007;8:959–969.CrossRefPubMedGoogle Scholar
  30. 30.
    Nichols JT, Miyamoto A, Olsen SL, D'Souza B, Yao C, Weinmaster G: DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 2007;176:445–458.CrossRefPubMedGoogle Scholar
  31. 31.
    Steiner H, Fluhrer R, Haass C: Intramembrane proteolysis by {gamma}-secretase. J Biol Chem 2008;283:29627–29631.CrossRefPubMedGoogle Scholar
  32. 32.
    Six E, Ndiaye D, Laabi Y, Brou C, Gupta-Rossi N, Israel A, Logeat F: The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase. Proc Natl Acad Sci USA 2003;100:7638–7643.CrossRefPubMedGoogle Scholar
  33. 33.
    Borggrefe T, Oswald F: The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 2009. Epub ahead of print.Google Scholar
  34. 34.
    McElhinny AS, Li JL, Wu L: Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways. Oncogene 2008;27:5138–5147.CrossRefPubMedGoogle Scholar
  35. 35.
    Fischer A, Gessler M: Delta Notch and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucl Acids Res 2007;35:4583–4596.CrossRefPubMedGoogle Scholar
  36. 36.
    Esni F, Ghosh B, Biankin AV, Lin JW, Albert MA, Yu X, MacDonald RJ, Civin CI, Real FX, Pack MA, Ball DW, Leach SD: Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 2004;131:4213–4224.CrossRefPubMedGoogle Scholar
  37. 37.
    Kimura K, Satoh K, Kanno A, Hamada S, Hirota M, Endoh M, Masamune A, Shimosegawa T: Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice. Cancer Sci 2007;98:155–162.CrossRefPubMedGoogle Scholar
  38. 38.
    Guo X, Wang X-F: Signaling cross-talk between TGF-[beta]/BMP and other pathways. Cell Res 2009;19:71–88.CrossRefPubMedGoogle Scholar
  39. 39.
    Holderfield MT, Hughes CCW: Crosstalk between vascular endothelial growth factor, Notch, and transforming growth factor-{beta} in vascular morphogenesis. Circ Res 2008;102:637–652.CrossRefPubMedGoogle Scholar
  40. 40.
    Krejcí A, Bernard F, Housden B, Collins S, Bray S: Direct response to Notch activation: signaling crosstalk and incoherent logic. Sci Signal 2009;2:ra1.Google Scholar
  41. 41.
    Shih I-M, Wang T-L: Notch signaling, {gamma}-secretase inhibitors, and cancer therapy. Cancer Res 2007;67:1879–1882.CrossRefPubMedGoogle Scholar
  42. 42.
    Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK: Essential role of endothelial Notch1 in angiogenesis. Circulation 2005;111:1826–1832.CrossRefPubMedGoogle Scholar
  43. 43.
    Doi H, Iso T, Sato H, Yamazaki M, Matsui H, Tanaka T, Manabe I, Arai M, Nagai R, Kurabayashi M: Jagged1-selective Notch signaling induces smooth muscle differentiation via a rbp-j{kappa}-dependent pathway. J Biol Chem 2006;281:28555–28564.CrossRefPubMedGoogle Scholar
  44. 44.
    Dufraine J, Funahashi Y, Kitajewski J: Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 2008;27:5132–5137.CrossRefPubMedGoogle Scholar
  45. 45.
    Gridley T: Notch signaling in vascular development and physiology. Development 2007;134:2709–2718.CrossRefPubMedGoogle Scholar
  46. 46.
    Trindade A, Ram Kumar S, Scehnet JS, Lopes-da-Costa L, Becker J, Jiang W, Liu R, Gill PS, Duarte A: Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos. Blood 2008;112:1720–1729.CrossRefPubMedGoogle Scholar
  47. 47.
    MacKenzie F, Duriez P, Larrivee B, Chang L, Pollet I, Wong F, Yip C, Karsan A: Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-J{kappa}. Blood 2004;104:1760–1768.CrossRefPubMedGoogle Scholar
  48. 48.
    Truty M, Urrutia R: Basics of TGF-beta and pancreatic cancer. Pancreatology 2007;7:423–435.CrossRefPubMedGoogle Scholar
  49. 49.
    Armulik A, Abramsson A, Betsholtz C: Endothelial/pericyte interactions. Circ Res 2005;97:512–523.CrossRefPubMedGoogle Scholar
  50. 50.
    Blokzijl A, Dahlqvist C, Reissmann E, Falk A, Moliner A, Lendahl U, Ibanez CF: Cross-talk between the Notch and TGF-{beta} signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J Cell Biol 2003;163:723–728.CrossRefPubMedGoogle Scholar
  51. 51.
    Niimi H, Pardali K, Vanlandewijck M, Heldin C-H, Moustakas A: Notch signaling is necessary for epithelial growth arrest by TGF-{beta}. J Cell Biol 2007;176:695–707.CrossRefPubMedGoogle Scholar
  52. 52.
    Itoh F, Itoh S, Goumans M, Valdimarsdottir G, Iso T, Dotto G, Hamamori Y, Kedes L, Kato M, ten Dijke P: Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells. EMBO J 2004;23:541–551.CrossRefPubMedGoogle Scholar
  53. 53.
    Thurston G, Kitajewski J: VEGF and delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer 2008;99:1204–1209.CrossRefPubMedGoogle Scholar
  54. 54.
    Siekmann AF, Lawson ND: Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 2007;445:781–784.CrossRefPubMedGoogle Scholar
  55. 55.
    Banerjee S, Mehta S, Haque I, Sengupta K, Dhar K, Kambhampati S, Van Veldhuizen PJ, Banerjee SK: VEGF-A165 induces human aortic smooth muscle cell migration by activating Neuropilin-1-VEGFR1-PI3K Axis†. Biochemistry 2008;47:3345–3351.CrossRefPubMedGoogle Scholar
  56. 56.
    Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD,.Wiegand SJ: Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 2007;104:3219–3224.CrossRefPubMedGoogle Scholar
  57. 57.
    Jiang Z, Song J, Qi F, Xiao A, An X, Liu N-a, Zhu Z, Zhang B, Lin S: exdpf is a key regulator of exocrine pancreas development controlled by retinoic acid and ptf1a in Zebrafish. PLoS Biol 2008;6:e293.CrossRefPubMedGoogle Scholar
  58. 58.
    Bernardo AS, Hay CW, Docherty K: Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic [beta] cell. Mol Cell Endocrinol 2008;294:1–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Fukuda A, Kawaguchi Y, Furuyama K, Kodama S, Horiguchi M, Kuhara T, Kawaguchi M, Terao M, Doi R, Wright CVE, Hoshino M, Chiba T, Uemoto S: Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice. Diabetes 2008;57:2421–2431.CrossRefPubMedGoogle Scholar
  60. 60.
    Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, de Angelis MH, Lendahl U, Edlund H: Notch signalling controls pancreatic cell differentiation. Nature 1999;400:877–881.CrossRefPubMedGoogle Scholar
  61. 61.
    Pear W, Aster J: T cell acute lymphoblastic leukemia/lymphoma: a human cancer commonly associated with aberrant NOTCH1 signaling. Curr Opin Hematol 2004;11:426–433.CrossRefPubMedGoogle Scholar
  62. 62.
    Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD: Notch mediates TGF[alpha]-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 2003;3:565–576.CrossRefPubMedGoogle Scholar
  63. 63.
    Wagner M, Greten F, Weber C, Koschnick S, 1 Torsten Mattfeldt T, Deppert W, Kern H, Adler G, Roland M, Schmid R: A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev 2001;15(3):286–293.CrossRefPubMedGoogle Scholar
  64. 64.
    Büchler P, Gazdhar A, Schubert M, Giese N, Reber H, Hines O, Giese T, Ceyhan G, Müller M, Büchler M, Friess H: The Notch signaling pathway is related to neurovascular progression of pancreatic cancer. Ann Surg 2005;242:791–800.CrossRefPubMedGoogle Scholar
  65. 65.
    Doucas H, Mann C, Sutton C, Garcea G, Neal C, Berry D, Manson M: Expression of nuclear notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt. J Surg Oncol 2008;97:63–68.CrossRefPubMedGoogle Scholar
  66. 66.
    Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH: Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 2006;5:483–493.CrossRefPubMedGoogle Scholar
  67. 67.
    Wolfe M: Gamma-secretase modulators. Curr Alzheimer Res 2007;4:571–573.Google Scholar
  68. 68.
    Imbimbo B: Therapeutic potential of γ-secretase inhibitors and modulators. Curr Top Med Chem 2008;8:54–61.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Department of Medicine and Mayo Clinic Cancer Center, Mayo ClinicLaboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research UnitRochesterUSA

Personalised recommendations