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. NOTCH3 expression pattern is more restricted than the expression patterns of NOTCH1 and NOTCH2, with predominant expression of NOTCH3 in vascular smooth muscle cells, lymphocytes and the nervous system (reviewed by Bellavia et al. 2008). Based on the study of Notch3 knockout mice, Notch3 is not essential for embryonic development or fertility (Krebs et al. 2003).
<p>Germline gain-of-function NOTCH3 mutations are an underlying cause of the CADASIL syndrome - cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is characterized by degeneration and loss of vascular smooth muscle cells from the arterial wall, predisposing affected individuals to an early onset stroke (Storkebaum et al. 2011). NOTCH3 promotes survival of vascular smooth muscle cells at least in part by induction of CFLAR (c FLIP), an inhibitor of FASLG activated death receptor signaling. The mechanism of NOTCH3 mediated upregulation of CFLAR is unknown; it is independent of the NOTCH3 coactivator complex and involves an unelucidated crosstalk with the RAS/RAF/MAPK pathway (Wang et al. 2002).<p><p>In rat brain, NOTCH3 and NOTCH1 are expressed at sites of adult neurogenesis, such as the dentate gyrus (Irvin et al. 2001). NOTCH3, similar to NOTCH1, promotes differentiation of the rat adult hippocampus derived multipotent neuronal progenitors into astroglia (Tanigaki et al. 2001). NOTCH1, NOTCH2, NOTCH3, and their ligand DLL1 are expressed in neuroepithelial precursor cells in the neural tube of mouse embryos. Together, they signal to inhibit neuronal differentiation of neuroepithelial precursors. Expression of NOTCH3 in mouse neuroepithelial precursors is stimulated by growth factors BMP2, FGF2, Xenopus TGF beta5 - homologous to TGFB1, LIF, and NTF3 (Faux et al. 2001).<p>In mouse telencephalon, NOTCH3, similar to NOTCH1, promotes radial glia and neuronal progenitor phenotype. This can, at least in part be attributed to NOTCH mediated activation of RBPJ-dependent and HES5-dependent transcription (Dang et al. 2006).<p>In mouse spinal cord, Notch3 is involved in neuronal differentiation and maturation. Notch3 knockout mice have a decreased number of mature inhibitory interneurons in the spinal cord, which may be involved in chronic pain conditions (Rusanescu and Mao 2014).<p><p>NOTCH3 amplification was reported in breast cancer, where NOTCH3 promotes proliferation and survival of ERBB2 negative breast cancer cells (Yamaguchi et al. 2008), and it has also been reported in ovarian cancer (Park et al. 2006). NOTCH3 signaling is involved in TGF beta (TGFB1) signaling-induced eptihelial to mesenchimal transition (EMT) (Ohashi et al. 2011, Liu et al. 2014)<p><p>NOTCH3 indirectly promotes development of regulatory T cells (Tregs). NOTCH3 signaling activates pre-TCR-dependent and PKC-theta (PRKCQ)-dependent NF-kappaB (NFKB) activation, resulting in induction of FOXP3 expression (Barbarulo et al. 2011). Deregulated NOTCH3 and pre-TCR signaling contributes to development of leukemia and lymphoma (Bellavia et al. 2000, Bellavia et al. 2002).
View original pathway at:Reactome.</div>
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
Based on a study with mouse proteins, NOTCH3 receptor binds to DLL1 ligand (Shimizu et al. 2000). The interaction of DLL1 and NOTCH3 is implicated in functional differentiation of activated CD4+ T lymphocytes into type 1 helper T cells (Th1) (Maekawa et al. 2003). The effect of Fringe-mediated modification of NOTCH3 on its interaction with DLL1 is poorly studied (Hou et al. 2012).
Based on an analogy with Drosophila Notch and its intracellular cleavage product NICD, it is believed that the cytosolic NICD3 translocates to the nucleus (Lecourtois and Schweisguth 1998, Struhl and Adachi 1998).
Binding of NOTCH3 receptor to DLL4 ligand has not been directly demonstrated. DLL4 and NOTCH3 are expressed on neighboring cells in retina (Claxton and Fruttiger 2004) and in endothelium/blood (Indraccolo et al. 2009), and DLL4 significantly and specifically increases NOTCH3 signaling (Indraccolo et al. 2009).
Based on an analogy with NOTCH1 and NOTCH2, and on studies of Drosophila Notch, NOTCH ligands DLL1, DLL4, JAG1 and JAG2 are assumed to undergo ubiquitination and endocytosis after binding to NOTCH3 in trans. Ubiquitination of DLL/JAG ligands in mammals is performed by orthologues of Drosophila Mindbomb, MIB1, possibly MIB2, and possibly orthologues of Drosophila Neuralized, NEURL and NEURL1B.
Ligand binding induces a conformational change in NOTCH3, probably through mechanical pulling of NOTCH3 triggered by endocytosis of the receptor-attached ubiquitinated ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH3 and triggers cleavage of NOTCH3 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH3 fragment NEXT3 (Groot et al. 2014). 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, containing either PSEN1 (presenilin-1) or PSEN2 (presenilin-2) as the catalytic subunit, which releases the intracellular domain NICD3 into the cytosol (Groot et al. 2014).
HEYL gene expression is stimulated by NOTCH3 (Maier and Gessler 2000). In developing mouse embryos, Notch3 expression overlaps with HeyL expression in vascular smooth muscle cells and in the thymus (Leimeister et al. 2000).
Based on studies in a mouse system, HES1 gene expression is directly stimulated by the NOTCH3 coactivator complex (Lin et al. 2002, Shimizu et al. 2002). Activated STAT1 directly enhances HES1 transcription induced by NICD3 (Boelens et al. 2014).
Based on studies in mouse, NOTCH3 intracellular domain (NICD3), likely in complex with RBPJ and MAML (MAML1, MAML2 or MAML3), positively regulates transcription from the HES5 gene promoter. While HES5 promoter contains RBPJ binding elements, direct binding of the NOTCH3 coactivator complex to the HES5 promoter has not been demonstrated (Lin et al. 2002, Shimizu et al. 2002). Studies in rats suggest that NOTCH3-mediated upregulation of HES5 plays a key role in the development of pulmonary arterial hypertension. NOTCH3 and HES5 are both expressed in vascular smooth muscle cells of small pulmonary arteries of human and rat lungs, with NOTCH3 and HES5 levels increased in hypertensive human and rat lung tissues (Li et al. 2009).
In the nucleus, NICD3 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind) proteins MAML1, MAML2 or MAML3 (possibly also MAMLD1). NICD3:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (Lin et al. 2002).
Besides NICD3, RBPJ and MAML, NOTCH3 coactivator complex likely includes other proteins shown as components of the NOTCH1 coactivator complex. Since disruption of the RBPJ:NCOR corepressor and MAML-mediated recruitment of transcriptional activators has not been studied in the context of NICD3, it is not shown here. More details are available in the pathway Signaling by NOTCH1.
Many NOTCH-regulated genes have paired RBPJ-binding sites in their promoters, in head-to-head arrangement, and require cooperative formation of dimeric NOTCH transcription complexes for transcriptional activation (Nam et al. 2007).
NOTCH3 coactivator complex, composed of at least NICD3 (NOTCH3 intracellular domain), RBPJ and MAML (MAML1, MAML2 or MAML3; possibly MAMLD1), directly binds to RBPJ elements in the HES1 gene promoter (Lin et al. 2002).
Based on a study involving mouse and rat proteins and DNA, NOTCH3 coactivator complex positively regulates transcription of HEY1 (HRT1). Direct binding of NOTCH3 to the HEY1 gene promoter has not been demonstrated (Wang et al. 2002). STAT1 directly enhances HEY1 gene transcription induced by NICD3. In breast cancer, stromal cells secrete RNA-containing exosomes. Upon uptake of exosomes by breast cancer cells, STAT1-dependent antiviral signaling is initiated. Stromal cells also express JAG1 ligand on their surface and, in parallel to STAT1 signaling, activate NOTCH3 signaling in NOTCH3-expressing breast cancer cells. Synergistic activation of NOTCH3 and STAT1 increases breast cancer radiation resistance (Boelens et al. 2014).
Based on a study involving mouse and rat proteins and DNA, NOTCH3 coactivator complex positively regulates transcription of HEY2 (HRT2). Direct binding of NOTCH3 to the HEY2 gene promoter has not been demonstrated (Wang et al. 2002).
Based on studies in mice, expression of FABP7 (BLBP) in radial glia is positively regulated by NOTCH1 and NOTCH3 during neuronal migration (Anthony et al. 2005, Keilani and Sugaya 2008). The promoter of the mouse Fabp7 gene contains an Rbpj binding site needed for Fabp7 expression (Anthony et al. 2005). Several sites related to the consensus RBPJ binding sequence exist in the human FABP7 gene promoter.
Based on studies in mice, NOTCH3 intracellular domain NICD3 positively regulates transcription of the PTCRA gene, encoding pre-T-cell receptor alpha (pre-TCR-alpha or pTalpha). NICD3-mediated induction of PTCRA transcription is RBPJ and MAML dependent, and the PTCRA promoter contains several RBPJ-binding sites (Talora et al. 2003, Bellavia et al. 2007). IK1, splicing isoform of the transcription factor Ikaros (IKZF1), competes with RBPJ for binding to the PTCRA promoter and inhibits PTCRA transcription. NOTCH3, through pre-TCR signaling, stimulates expression of the RNA binding protein HuD, which promotes splicing of IKZF1 into dominant negative isoforms. These dominant negative isoforms of IKZF1 heterodimerize with IK1, preventing its binding to target DNA sequences and thus contributing to sustained transcription of PTCRA (Bellavia et al. 2007, reviewed by Bellavia, Mecarrozzi, Campese, Grazioli, Gulino and Screpanti 2007).
Based on studies in mice, NOTCH3 coactivator complex binds to RBPJ binding sites in the promoter of the PTCRA gene, encoding pre-TCR-alpha (Bellavia et al. 2007).
IK1, the splicing isoform 1 of the transcription factor Ikaros (IKZF1), binds to the promoter of the PTCRA gene, encoding pre-TCR-alpha. IK1-bindining sites overlap with RBPJ-binding sites. Therefore, IK1 competes with NOTCH3 coactivator complexes for binding to the PTCRA promoter (Bellavia et al. 2007). It is unknown which IK1 heterodimerization partners are involved in binding to the PTCRA promoter.
Based on the findings that the NOTCH3 coactivator complex component RBPJ (CSL) binds to RBPJ response elements in the promoter of the HEYL gene (Geimer Le Lay et al. 2014) and that HEYL gene expression is stimulated by NOTCH3 (Maier and Gessler 2000) and overlaps with NOTCH3 expression in vascular smooth muscle cells and the thymus (Leimeister et al. 2000), it can be concluded that the NOTCH3 coactivator complex binds the promoter of the HEYL gene.
YBX1 (YB-1) binds to EGF repeats in the extracellular domain of NOTCH3 (Rauen et al. 2009). While YBX1 is extensively studied as a protein involved in mRNA processing, it is also secreted by mesangial cells and monocytes during inflammation and can act as an extracellular mitogen (Frye et al. 2009).
Binding of NOTCH3 to YBX1 (YB-1) triggers cleavage of NOTCH3 by the gamma-secretase complex. The exact steps of YBX1-mediated NOTCH3 activation are not known. The gamma-secretase complex releases NOTCH3 intracellular domain (NICD3), leading to activation of NOTCH3 target genes downstream of YBX1 (Rauen et al. 2009).
Based on studies in mice, the intracellular domain of NOTCH3, NICD3, binds to transforming acidic coiled-coil protein-3 (TACC3). The interaction involves the ankyrin repeats of NOTCH3. The two proteins co-localize in the cytosol and possibly in the nucleus. TACC3 is implicated as a negative regulator of NOTCH signaling and may compete with NOTCH binding to RPBJ (Bargo et al. 2010).
Binding of the NOTCH3 coactivator complex to RBPJ response elements in the promoter of the DLGAP5 gene stimulates DLGAP5 transcription. DLGAP5 is involved in G2/M transition and is overexpressed in ovarian cancer cells. NOTCH3 gene is frequently amplified in ovarian cancer (Chen et al. 2012).
NOTCH3 coactivator complex binds the RBPJ (CSL) response elements in the promoter of the DLGAP5 gene. Two adjacent CSL-binding motifs in the DLGAP5 promoter, which are 6 bp apart, are both necessary for NOTCH3-mediated induction of DLGAP5 transcription (Chen et al. 2012).
EGFR phosphorylates intracellular domain of NOTCH3 (NICD3) on an unknown tyrosine residue. EGFR signaling inhibits NICD3-mediated transcription. It is not known whether EGFR-mediated phosphorylation of NICD3 affects NICD3 nuclear translocation or the formation of the NOTCH3 coactivator complex. Erlotinib treatment, which inhibits EGFR activation, results in increased NOTCH3 signaling and induction of stem-like phenotype in treated cells (Arasada et al. 2014).
The intracellular domain of NOTCH3 (NICD3) co-immunoprecipitates with ligand activated, autophosphorylated EGFR. Binding of NOTCH3 to EGFR is inhibited by erlotinib treatment, which prevents EGFR activation (Arasada et al. 2014).
NOTCH3 coactivator complex, composed of at least NICD3 (NOTCH3 intracellular domain), RBPJ and MAML (MAML1, MAML2 or MAML3; possibly MAMLD1), directly binds to RBPJ elements in the HES1 gene promoter (Lin et al. 2002). STAT1 can bind to STAT response elements in the HES1 gene promoter and enhance HES1 transcription induced by NICD3. In breast cancer, stromal cells secrete RNA-containing exosomes. Upon uptake of exosomes by breast cancer cells, STAT1-dependent antiviral signaling is initiated. Stromal cells also express JAG1 ligand on their surface and, in parallel to STAT1 signaling, activate NOTCH3 signaling in NOTCH3-expressing breast cancer cells. Synergistic activation of NOTCH3 and STAT1 increases breast cancer radiation resistance (Boelens et al. 2014).
PBX1 gene transcription is directly stimulated by the NOTCH3 coactivator complex (Park et al. 2008). NOTCH3 gene is amplified in high-grade ovarian serous carcinoma and NOTCH3 overexpression contributes to cancer cell growth (Park et al. 2006). Overexpression of NOTCH3 in high-grade ovarian serous carcinoma correlates with overexpression of PBX1 (Park et al. 2006, Park et al. 2008). PBX1 gene encodes a homeodomain transcription factor PBX1 which is a B cell leukemia (B-ALL) oncogene (Nourse et al. 1990, Kamps et al. 1991) and is also overexpressed in melanoma (Shiraishi et al. 2007).
PLXND1 gene transcription is stimulated by NOTCH1 and NOTCH3 coactivator complexes. PLXND1 encodes the semaphorin receptor Plexin-D1, involved in neuronal migration as well as cancer cell invasiveness (Rehman et al. 2016).
PLXND1 gene promoter possesses an RBPJ-binding site which is necessary for NOTCH1 and NOTCH3-mediated induction of PLXND1 transcription. It is therefore concluded that NOTCH1 and NOTCH3 co-activator complexes directly bind to the PLXND1 gene promoter (Rehman et al. 2016).
The NOTCH3 coactivator complex directly stimulates WWC1 gene transcription. WWC1 gene encodes the protein Kibra, involved in Hippo signaling. NOTCH3-mediated induction of WWC1 positively regulates Hippo signaling and inhibits epithelial-to-mesenchymal transition (EMT) in triple negative breast cancer cells (Zhang et al. 2016).
The WWC1 (Kibra) gene promoter region contains two RBPJ-binding sites, one on the sense strand and one on the antisense strand. The NOTCH3 coactivator complex binds to the RBPJ-binding site on the antisense strand (Zhang et al. 2016).
WWP2, an E3 ubiquitin ligase, can interact with NOTCH3 cleavage products NEXT3 and NICD3 in the cytosol. The interaction involves the PPPY motif in the PEST domain of NOTCH3 (Jung et al. 2014).
WWP2, an E3 ubiquitin ligase, ubiquitinates NOTCH3 cleavage fragments NEXT3 and NICD3 in the cytosol, targeting them for lysosome-mediated degradation. WWP2 thus negatively regulates NOTCH3 signaling. WWP2 is a putative tumor suppressor whose deletions have been reported in the majority of ovarian carcinomas (Jung et al. 2014).
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coactivator
complex:PLXND1 genecoactivator
complexescoactivator
complex:p-Y701-STAT1 dimer:HES1 geneAnnotated Interactions
coactivator
complex:PLXND1 genecoactivator
complex:PLXND1 genecoactivator
complexescoactivator
complexescoactivator
complex:p-Y701-STAT1 dimer:HES1 genecoactivator
complex:p-Y701-STAT1 dimer:HES1 geneBesides NICD3, RBPJ and MAML, NOTCH3 coactivator complex likely includes other proteins shown as components of the NOTCH1 coactivator complex. Since disruption of the RBPJ:NCOR corepressor and MAML-mediated recruitment of transcriptional activators has not been studied in the context of NICD3, it is not shown here. More details are available in the pathway Signaling by NOTCH1.
Many NOTCH-regulated genes have paired RBPJ-binding sites in their promoters, in head-to-head arrangement, and require cooperative formation of dimeric NOTCH transcription complexes for transcriptional activation (Nam et al. 2007).