Similar to NOTCH1, NOTCH3 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH3, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH3, NICD3, into the cytosol. NICD3 subsequently traffics to the nucleus where it acts as a transcriptional regulator.
Yamaguchi N, Oyama T, Ito E, Satoh H, Azuma S, Hayashi M, Shimizu K, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Ohwada S, Tatsuta K, Inoue J, Semba K, Watanabe S.; ''NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells.''; PubMedEurope PMCScholia
Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M.; ''Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling.''; PubMedEurope PMCScholia
Andersson ER, Lendahl U.; ''Therapeutic modulation of Notch signalling--are we there yet?''; PubMedEurope PMCScholia
Barbarulo A, Grazioli P, Campese AF, Bellavia D, Di Mario G, Pelullo M, Ciuffetta A, Colantoni S, Vacca A, Frati L, Gulino A, Felli MP, Screpanti I.; ''Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription.''; PubMedEurope PMCScholia
Rusanescu G, Mao J.; ''Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord.''; PubMedEurope PMCScholia
Claxton S, Fruttiger M.; ''Periodic Delta-like 4 expression in developing retinal arteries.''; PubMedEurope PMCScholia
Shimizu K, Chiba S, Saito T, Kumano K, Hamada Y, Hirai H.; ''Functional diversity among Notch1, Notch2, and Notch3 receptors.''; PubMedEurope PMCScholia
Zhang X, Liu X, Luo J, Xiao W, Ye X, Chen M, Li Y, Zhang GJ.; ''Notch3 inhibits epithelial-mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells.''; PubMedEurope PMCScholia
Irvin DK, Zurcher SD, Nguyen T, Weinmaster G, Kornblum HI.; ''Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain development.''; PubMedEurope PMCScholia
Jung JG, Stoeck A, Guan B, Wu RC, Zhu H, Blackshaw S, Shih IeM, Wang TL.; ''Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer.''; PubMedEurope PMCScholia
Wang W, Prince CZ, Mou Y, Pollman MJ.; ''Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.''; PubMedEurope PMCScholia
Ohashi S, Natsuizaka M, Naganuma S, Kagawa S, Kimura S, Itoh H, Kalman RA, Nakagawa M, Darling DS, Basu D, Gimotty PA, Klein-Szanto AJ, Diehl JA, Herlyn M, Nakagawa H.; ''A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors.''; PubMedEurope PMCScholia
Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, Eberhart CG, Shih IeM, Wang TL.; ''Notch3 gene amplification in ovarian cancer.''; PubMedEurope PMCScholia
Storkebaum E, Quaegebeur A, Vikkula M, Carmeliet P.; ''Cerebrovascular disorders: molecular insights and therapeutic opportunities.''; PubMedEurope PMCScholia
Groot AJ, Habets R, Yahyanejad S, Hodin CM, Reiss K, Saftig P, Theys J, Vooijs M.; ''Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins.''; PubMedEurope PMCScholia
Maier MM, Gessler M.; ''Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes.''; PubMedEurope PMCScholia
Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G, Lendahl U, Fehling HJ, Hayday AC, Frati L, von Boehmer H, Gulino A, Screpanti I.; ''Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis.''; PubMedEurope PMCScholia
Dang L, Yoon K, Wang M, Gaiano N.; ''Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon.''; PubMedEurope PMCScholia
Indraccolo S, Minuzzo S, Masiero M, Pusceddu I, Persano L, Moserle L, Reboldi A, Favaro E, Mecarozzi M, Di Mario G, Screpanti I, Ponzoni M, Doglioni C, Amadori A.; ''Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy.''; PubMedEurope PMCScholia
Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S.; ''Human ligands of the Notch receptor.''; PubMedEurope PMCScholia
Bellavia D, Checquolo S, Campese AF, Felli MP, Gulino A, Screpanti I.; ''Notch3: from subtle structural differences to functional diversity.''; PubMedEurope PMCScholia
Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H, Ter Brugge PJ, Jonkers J, Slingerland J, Minn AJ.; ''Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.''; PubMedEurope PMCScholia
Liu L, Chen X, Wang Y, Qu Z, Lu Q, Zhao J, Yan X, Zhang H, Zhou Y.; ''Notch3 is important for TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1.''; PubMedEurope PMCScholia
Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H, Honjo T.; ''Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.''; PubMedEurope PMCScholia
Krebs LT, Xue Y, Norton CR, Sundberg JP, Beatus P, Lendahl U, Joutel A, Gridley T.; ''Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation.''; PubMedEurope PMCScholia
Rehman M, Gurrapu S, Cagnoni G, Capparuccia L, Tamagnone L.; ''PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells.''; PubMedEurope PMCScholia
Arasada RR, Amann JM, Rahman MA, Huppert SS, Carbone DP.; ''EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling.''; PubMedEurope PMCScholia
Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman ES, Hayday AC, Lendahl U, Frati L, Gulino A, Screpanti I.; ''Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice.''; PubMedEurope PMCScholia
Chen X, Thiaville MM, Chen L, Stoeck A, Xuan J, Gao M, Shih IeM, Wang TL.; ''Defining NOTCH3 target genes in ovarian cancer.''; PubMedEurope PMCScholia
Park JT, Shih IeM, Wang TL.; ''Identification of Pbx1, a potential oncogene, as a Notch3 target gene in ovarian cancer.''; PubMedEurope PMCScholia
Matsumoto A, Onoyama I, Sunabori T, Kageyama R, Okano H, Nakayama KI.; ''Fbxw7-dependent degradation of Notch is required for control of "stemness" and neuronal-glial differentiation in neural stem cells.''; PubMedEurope PMCScholia
In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009).
The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).
In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
Ligand binding induces a conformational change in the NOTCH3, probably through mechanical pulling of NOTCH3 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH3 and results in cleavage of NOTCH3 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH3 fragment NEXT3. The extracellular NOTCH3 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD3 into the cytosol.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1980148
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The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).
In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
Annotated Interactions