Similar to NOTCH1, NOTCH4 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH4, 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 NOTCH4, NICD4, into the cytosol. NICD4 subsequently traffics to the nucleus where it acts as a transcriptional regulator.
Raafat A, Bargo S, McCurdy D, Callahan R.; ''The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis.''; PubMedEurope PMCScholia
Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, Borisenko V, Feirt N, Podgrabinska S, Shiraishi K, Chawengsaksophak K, Rossant J, Accili D, Skobe M, Kitajewski J.; ''Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression.''; PubMedEurope PMCScholia
Bargo S, Raafat A, McCurdy D, Amirjazil I, Shu Y, Traicoff J, Plant J, Vonderhaar BK, Callahan R.; ''Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats.''; PubMedEurope PMCScholia
Raafat A, Bargo S, Anver MR, Callahan R.; ''Mammary development and tumorigenesis in mice expressing a truncated human Notch4/Int3 intracellular domain (h-Int3sh).''; PubMedEurope PMCScholia
Raafat A, Zoltan-Jones A, Strizzi L, Bargo S, Kimura K, Salomon D, Callahan R.; ''Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis.''; PubMedEurope PMCScholia
Qian C, Liu F, Ye B, Zhang X, Liang Y, Yao J.; ''Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling.''; PubMedEurope PMCScholia
Tang Y, Urs S, Liaw L.; ''Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.''; PubMedEurope PMCScholia
James AC, Szot JO, Iyer K, Major JA, Pursglove SE, Chapman G, Dunwoodie SL.; ''Notch4 reveals a novel mechanism regulating Notch signal transduction.''; PubMedEurope PMCScholia
Kusano S, Raab-Traub N.; ''An Epstein-Barr virus protein interacts with Notch.''; PubMedEurope PMCScholia
Fukusumi T, Guo TW, Sakai A, Ando M, Ren S, Haft S, Liu C, Amornphimoltham P, Gutkind JS, Califano JA.; ''The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma.''; PubMedEurope PMCScholia
Li Y, Wu S, Pu J, Huang X, Zhang P.; ''Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-β signalling pathway.''; PubMedEurope PMCScholia
Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J.; ''Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene.''; PubMedEurope PMCScholia
Welcker M, Clurman BE.; ''FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.''; PubMedEurope PMCScholia
Bonyadi Rad E, Hammerlindl H, Wels C, Popper U, Ravindran Menon D, Breiteneder H, Kitzwoegerer M, Hafner C, Herlyn M, Bergler H, Schaider H.; ''Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors.''; PubMedEurope PMCScholia
Aste-Amézaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT, Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E, Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang H, Wang F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE.; ''Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors.''; PubMedEurope PMCScholia
MacKenzie F, Duriez P, Wong F, Noseda M, Karsan A.; ''Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways.''; PubMedEurope PMCScholia
Shawber CJ, Das I, Francisco E, Kitajewski J.; ''Notch signaling in primary endothelial cells.''; PubMedEurope PMCScholia
Das I, Craig C, Funahashi Y, Jung KM, Kim TW, Byers R, Weng AP, Kutok JL, Aster JC, Kitajewski J.; ''Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.''; PubMedEurope PMCScholia
Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J.; ''SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.''; PubMedEurope PMCScholia
Ramakrishnan G, Davaakhuu G, Chung WC, Zhu H, Rana A, Filipovic A, Green AR, Atfi A, Pannuti A, Miele L, Tzivion G.; ''AKT and 14-3-3 regulate Notch4 nuclear localization.''; PubMedEurope PMCScholia
Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, Bessho Y, Kageyama R, Suda T, Nakayama KI.; ''Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development.''; PubMedEurope PMCScholia
Gallahan D, Callahan R.; ''Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors.''; PubMedEurope PMCScholia
Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI.; ''Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line.''; PubMedEurope PMCScholia
Lai PY, Tsai CB, Tseng MJ.; ''Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes.''; PubMedEurope PMCScholia
Simões BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, Santiago-Gómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB.; ''Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.''; PubMedEurope PMCScholia
Robbins J, Blondel BJ, Gallahan D, Callahan R.; ''Mouse mammary tumor gene int-3: a member of the notch gene family transforms mammary epithelial cells.''; PubMedEurope PMCScholia
Uyttendaele H, Ho J, Rossant J, Kitajewski J.; ''Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium.''; PubMedEurope PMCScholia
Andersson ER, Lendahl U.; ''Therapeutic modulation of Notch signalling--are we there yet?''; PubMedEurope PMCScholia
Raafat A, Lawson S, Bargo S, Klauzinska M, Strizzi L, Goldhar AS, Buono K, Salomon D, Vonderhaar BK, Callahan R.; ''Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; 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
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; 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 NOTCH4, probably through mechanical pulling of NOTCH4 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH4 and results in cleavage of NOTCH4 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH4 fragment NEXT4. The extracellular NOTCH4 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
NEXT4 fragment of NOTCH4 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD4 into the cytosol.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1980150
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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