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Canonical Notch Signaling Pathway

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The Notch signal protein receptors are produced at ER, in Golgi are cleaved by a furin-like protease at S1 site, generating a heterodimeric receptor which is non-covalently expressed on the cell surface[11]. The canonical Notch signaling initiate along with cell to cell ligands and receptors interaction which is non-covalently binding. With the binding successive cleavages occur in the transmembrane region of Notch protein, at S2 cleavage site Notch receptor by an ADAM (a disintegrin and metalloproteinase) family protease decomposed, then the intracellular portion of the transmembrane Notch fragment is linked by mono-ubiquitylation, then endocytosis of the transmembrane fragment of the Notch protein contribute to the third cleavage at S3 site by γ-secretase and then liberates Notch intracellular domain(NIC), makes it entry[12]. However, in the absence of NIC, CSL may bind with ubiquitous co-repressor (CoR) proteins and histone deacetylases to repress transcription of some target genes. The mechanism of this process is NIC entry in the nucleus interacts with CSL and changes the conformation of CSL. When the conformation changes it can recruit co-activators and prevent co-repressor approaching.

In addition, a series of co-activators assists the compound leading to transcription activate of the downstream target gene and expression. Such as the target gene Hes family, VEGF, Cox-2, and MMP-9 which are expressed proteins mediating and participating in many important life processes[13]. The Notch signaling regulates cancer cell differentiation[14],which exerts it function often with relate signaling pathway[15]. So it will contribute to cross-talks reaction and make the complex result.

With prolonged in studying of the Notch signaling many new data are reported. A novel and conserved Rabgeranylgeranyltransferase (RabGGT)-a-like subunit which is essential for Notch signaling-mediated processing. The RabGGT affects Delta in the secretory pathway. Temp a novel gene which is a Notch signaling player. The novel gene encodes protein which form a subunit of the RabGGT[16]. So the gene of temp can regulate Notch signaling pathway often uses in regulating Notch signaling.

The canonical Notch signaling pathway involved in T-cell acute lymphoblastic leukemia (T-ALL) and small molecule γ- secretase inhibitors (GSIs) can effectively block Notch signaling in T-ALL. So exploits it as a target therapy in T-ALL disease, cancer. In addition other special antibody binding with receptors leading to Notch signaling pathway inactive. The target gene expression proteins are modified by endoplasmic reticulum and Golgi complex. The mature proteins can via autocrine and paracrine pathway exert it’s function.

Non-canonical Notch Signaling pathway

With the development of Notch signaling pathway many labs indicate that except for the canonical pathway their existence of another pathway which plays an important role in many processes calls non-canonical Notch signaling [17, 18]. The evidence has emerged for the non-canonical activation of Notch signaling. The non-canonical Notch signaling has two types. The type-1 is the ligands binding with receptors then release NIC enter in the nucleus and transduce the pathway independent CSL interactions. The type-2 is not involving receptors cleavage completely devoid of γ-secretase mediates cleavage of Notch receptor and CSL independent in signal transduction. The non-canonical Notch signaling pathway has many important research results. Such as regulates the angiogenesis[19] and breast tumorigenesis[20]and cells undifferentiated in the early stage[21]. In addition the pituitary gland could regulate by the non-canonical ligand Delta-Like protein 1 so the non-canonical Notch signaling also regulate various important processes.

The latest study reveals that IL-6 is a novel non-canonical Notch target gene in breast tumor cells, and the p53 can regulate this pathway[20]. Many of the cell have intrinsic functions of Notch occur through non-canonical signaling pathway which regulation of these processes are likely to occurs through NF- κB. Such as knocks out RBPJ in peripheral T cells, but still through this pathway activates and promotes proliferation of CD4+ T cells[22]. The epidermal growth factor-like protein Delta-like 1 (DLL1) which is considered a non-canonical ligand and regulates multiple differentiation processes.

The most difference between canonical Notch signaling pathway and non-canonical Notch signaling pathway is NIC whether binding with CSL. The data reveal that non-canonical Notch signaling independent Notch activate[23]. The target gene of canonical Notch signaling pathway Hes-1 is expressed in non-canonical Notch signaling process. In addition to Hes-1, other Notch targets have also been reported to express independently of canonical Notch signaling.

Moreover, the non-canonical Notch signaling pathway executes the various cellular functions cross-talk with other pathways such as interacts with Wnt/β-catenin signaling in synergic or antagonistic way[21]. So this may be the unique characteristic of non-canonical Notch signaling pathway.

Notch Signaling pathway in induction of apoptosis.

Non-canonical Notch signaling pathway in regulating cell apoptosis

Non-canonical Notch signaling could regulate neglect-induced death in mammalian cells. The non-canonical Notch signaling participates in many life processes in organisms. Such as differentiation, development, proliferation, apoptosis et al. Because of the mechanism is not clearly understood and know it less than canonical Notch signaling. LR Perumalsamy et al study reveals that Notch intracellular domain (NIC) independent of CBF1/RBP-J regulates neglect-induced death in mammalian cells. NIC mammalian target of rapamycin complex-2 (mTORC2)-Akt cascade blocks the apoptotic response triggered in serum deprivation medium[24]. This suggests that no-canonical Notch signaling can regulate cell apoptosis.

In their research utilizes gene depletion and gene silence to understand Akts473 is the target which favors cell survival. The molecule mechanism of NIC regulates cell inhibition apoptosis may be through this process. The non-canonical Notch signaling is activated, then releases NIC which binding with PI3K. The phosphatidylinositol 3,4, 5-triphosphates (PIP3) generated through PI3K activity bind the PH domain of AKT enabling its translocation to the plasma membrane and subsequent phosphorylation on threonine 308 and serine 473 (T308and S473). In addition NIC and mTORC2 could regulate AKT phosphorylation then control the AKT S473, AKT phosphorylation that inhibit TSC1 and TSC2. So NIC can indirect determine cell fate.

Canonical Notch signaling pathway in regulating cell apoptosis

The role of Notch signaling in inducing cells apoptosis is sparking by many researchers, especially who study tumor. Ji-Hye Yoon suggests that 5 -Nitro-indirubinoxime a new derivative of indirubin that induces cell cycle arrest and apoptosis by down-regulating Notch-1 signaling. The expressions of Notch-1, Notch-3, and their ligands (Delta1,3, 4, and Jagged-2) are declined, but Notch-2 and Notch-4 expression have no effect. However, overexpression of Notch-1 inhibits 5 -NIO-induced apoptosis [13]. This indicates that Notch1 signaling downstream target gene expression could suppress cells apoptosis and maintain cell alive. Notch-1 can inhibit p53-mediated apoptosis through the PI3K-AKT -mTOR-eIF4E pathway[25]. In addition Notch signaling may prevent T cell apoptosis in negative selection.

From recent years data indicates that canonical Notch signaling pathway has an intimate relationship with apoptosis. Many papers report that inhibit Notch1 signaling will promote cells apoptosis. Inhibiting Notch signaling pathway by γ-secretase inhibitor (DAPT) can induce apoptosis in lung squamous cell carcinoma (SCC) cell line SK-MES-1DAPT induces apoptosis not only through caspase-dependent pathway but also caspase-independent pathway [26]. DAPT treatment could effectively suppress Notch signaling pathway then activates caspase-3, -6 and -7 and induction of apoptosis. The direct evidences suggest that inhibitor suppress γ-secretase will contribute to cell apoptosis [27]. Inhibition of γ-secretase lead to block Notch signaling and decline cell viability resulted from a G0/G1 cell cycle block. In order to prove Notch signaling pathway regulates beta cell apoptosis, GSI is utilized show that after treatment mouse islets a significant increase in apoptosis and increase Notch1 activation is associated with a protective effect in beta cell[7]. However, Shuangyou Liu et al indicates different cell treatment by GSI has different effect such as type 1 cells line, TALL1 and HSB2 induction of apoptosis, type 2 cells upregulates the expression of the anti-apoptotic gene Bcl-xl. So the GSI treatment may be unpredictable the result[28]. Thus, GSI could act as a point to further study cells apoptosis in the future.

Zhiwei Wang et al suggests down-regulation of Notch-1 and Jagged-1 expression by siRNA could induce apoptosis which is in part contributed to cells death[29]. In addition down-regulation of Notch-1 or Jagged-1 significantly inhibited NF-κB DNA binding activity. Down-regulation of Notch-1 by siRNA or GSI together with TW-37 treatment inhibited cell growth and induced apoptosis to a greater degree in pancreatic cancer cells compared with TW-37 treatment alone [30],but down-regulation of Notch-1 and Jagged-1expression will inhibit cells growth and lead to death. Recently, study demonstrates that Notch signaling protects retina from NF-κB and poly ADP ribose polymerase (PARP) mediates apoptosis under high-glucose stimulation through the activation of AKT. Notch signaling protects cells from PARP and NF-kB-induced apoptosis. Reducing Notch1 and ligand DLL4 may promote cells apoptosis. Furthermore, Notch1 signaling pathway can protect endothelial cells from apoptosis through NF-κB with AKT pathway[31]. So this study show Notch1/DLL4 signaling may play important role in regulating cell apoptosis. Inhibition of Notch1 signaling by specialties inhibitor will decline the target gene expression without inducing cell apoptosis[32]. That may demonstrate Notch1 signaling pathway in pro-apoptosis process play part function.

The Notch signaling pathway target gene expression proteins, such as VEGF via autocrine and paracrine binding with the VEGFR activates the recruitment of the PI3K conversion of 3-hydroxyl group of phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). The PIP3 can activate phosphoinositide-dependent kinase 1 (PDK1) turn into PIP2 and then recruitment of AKT phosphorylated threonine 308 and serine 473[33]. The AKT then suppressor of mTORC functions by tuberous sclerosis complexes 1 and 2 (TSC1 and TSC2). On the one hand the absence of Notch target gene product VEGF will block the PI3K/AKT /mTORC downstream pathway. So this will activate the Caspase family and substance PARP. It follows that cell shrinking, DNA fragmentation, cell cycle arrest, membrane blebbing and apoptosis at last. On the other hand with the Notch target gene product VEGF will activate the mTOR1 then contribute to regulate cell growth and survival.

The study demonstrates that Notch signaling pathway takes part in anti-apoptosis processing. Under different stimulation the Notch signaling may suppress apoptosis partly. The mechanism of which Notch signaling suppresses apoptosis through activate AKT protection non-transformed breast epithelial cell from apoptosis [34]. In addition, the evidence suggests that Notch signaling suppress of adult human and mouse pancreatic islet cells[35]. So Notch signaling pathway activate or restrain may affect cells fate.

Conclusions and Future Directions

In this review we highlights the member of Notch signaling pathway and the function of regulating cells fate. As apoptosis is a important life phenomenon, studying this process will promote the development of life sciences. Recent years many researchers focus on apoptosis especially in tumor cells. Notch signaling pathway play important role in modulating cells apoptosis. The common way to study the function of this pathway often block Notch signaling activation and knock down Notch target gene to measurement cell apoptosis. The GSI often be applied suppression γ-. secretase in Notch signaling. Some data suggest that suppress Notch signaling will lead to cell apoptosis, but other data demonstrate inhibition pathway will contribute to cells anti-apoptosis. However, these opposite outcomes are not clear which needed further study. Many data suggest that the Notch signaling pathway is blocked and inactivated, the target gene will not be expressed. The absence of Notch target gene product will lead cell apoptosis. The molecule mechanism of Notch signaling in cells apoptosis may remain further elucidative. With the development of tumor studying, many researchers will pay more attention to cell apoptosis. It’s a good way to understand cells final fate. The mechanism of Notch signaling pathway regulates cell apoptosis will become a focus in the future and it could become a candidate for salivary gland adenocarcinoma therapeutics.

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