Signaling by NOTCH3

Stable Identifier
Homo sapiens
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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).

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).

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).

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).

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).

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)

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).

Literature References
PubMed ID Title Journal Year
11466430 Interactions between fibroblast growth factors and Notch regulate neuronal differentiation

Epa, R, Cappai, R, Bartlett, PF, Turnley, AM, Faux, CH

J. Neurosci. 2001
16508304 Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon

Wang, M, Gaiano, N, Dang, L, Yoon, K

Dev. Neurosci. 2006
10880446 Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice

Gaetano, C, Ruco, L, Alesse, E, Tiveron, C, Hayday, AC, Hoffman, ES, Bellavia, D, Frati, L, Balestri, A, Stoppacciaro, A, Vacca, A, Screpanti, I, Felli, MP, Tatangelo, L, Campese, AF, Lendahl, U, Gulino, A, Giovarelli, M

EMBO J. 2000
25164209 Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord

Mao, J, Rusanescu, G

J. Cell. Mol. Med. 2014
25080992 Notch3 is important for TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1

Lu, Q, Zhou, Y, Qu, Z, Zhang, H, Chen, X, Liu, L, Yan, X, Zhao, J, Wang, Y

Cancer Gene Ther. 2014
11891328 Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis

Cazzaniga, G, Biondi, A, von Boehmer, H, Fehling, HJ, Hayday, AC, Balestri, A, Campese, AF, Checquolo, S, Gulino, A, Frati, L, Screpanti, I, Lendahl, U, Bellavia, D

Proc. Natl. Acad. Sci. U.S.A. 2002
21508258 Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription

Vacca, A, Felli, MP, Ciuffetta, A, Barbarulo, A, Pelullo, M, Grazioli, P, Colantoni, S, Campese, AF, Gulino, A, Frati, L, Screpanti, I, Di Mario, G, Bellavia, D

J. Immunol. 2011
11182080 Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate

Honjo, T, Tashiro, K, Kurooka, H, Nogaki, F, Tanigaki, K, Takahashi, J

Neuron 2001
22030550 Cerebrovascular disorders: molecular insights and therapeutic opportunities

Storkebaum, E, Vikkula, M, Quaegebeur, A, Carmeliet, P

Nat. Neurosci. 2011
18758477 Notch3: from subtle structural differences to functional diversity

Screpanti, I, Checquolo, S, Felli, MP, Campese, AF, Gulino, A, Bellavia, D

Oncogene 2008
21890822 A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors

Kalman, RA, Nakagawa, M, Klein-Szanto, AJ, Gimotty, PA, Kimura, S, Basu, D, Itoh, H, Kagawa, S, Nakagawa, H, Naganuma, S, Darling, DS, Herlyn, M, Ohashi, S, Natsuizaka, M, Diehl, JA

Cancer Res. 2011
14595837 Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation

Gridley, T, Joutel, A, Beatus, P, Sundberg, JP, Krebs, LT, Norton, CR, Xue, Y, Lendahl, U

Genesis 2003
21349854 Fbxw7-dependent degradation of Notch is required for control of "stemness" and neuronal-glial differentiation in neural stem cells

Onoyama, I, Matsumoto, A, Sunabori, T, Okano, H, Nakayama, KI, Kageyama, R

J. Biol. Chem. 2011
11925448 Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis

Prince, CZ, Wang, W, Pollman, MJ, Mou, Y

J. Biol. Chem. 2002
16778208 Notch3 gene amplification in ovarian cancer

Davidson, B, Kurman, RJ, Park, JT, Zhang, Z, Mao, TL, Li, M, Wang, TL, Nakayama, K, Shih, IeM, Eberhart, CG

Cancer Res. 2006
18339869 NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells

Yanagisawa, Y, Shimizu, K, Inoue, J, Hayashi, M, Tatsuta, K, Nishikawa, A, Semba, K, Yamaguchi, N, Watanabe, S, Azuma, S, Ohwada, S, Kawamura, M, Oyama, T, Imai, J, Honma, R, Ito, E, Satoh, H

Cancer Res. 2008
11438922 Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain development

Nguyen, T, Weinmaster, G, Zurcher, SD, Kornblum, HI, Irvin, DK

J. Comp. Neurol. 2001
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