Notch signaling

The Notch pathway is an evolutionally conserved signaling pathway which plays an important role in diverse developmental and physiological processes. These include cell-fate determination, tissue patterning and morphogenesis, cell differentiation, proliferation and cell death. The Notch pathway is named after the Drosophila mutants that showed irregular notches of missing tissue at the insect wing blade tips. The Notch gene was cloned in 1985. Proteins of the Notch families are single-pass transmembrane proteins that function both as cell surface receptors and nuclear transcriptional regulators. Four Notch receptors (Notch 1-4) have been identified in mammals. Mature Notch receptors are non-covalent heterodimers consisting of an extracellular subunit (NEC) and a transmembrane subunit (NTM). NEC possess multiple EGF-like repeats and three specialized Lin-Notch repeats (LNR) that forms a tight hydrophobic interaction with extracellular stump of NTM. This region masks an A disintegrin and metalloprotease (ADAM) cleavage site. The region where these two subunits interact is called the heterodimerization domain (HD). Notch ligands are also transmembrane proteins with multiple EGF-like repeats, a short cytoplasmic tail and a specialized delta-serrate-lag2 (DSL) domain at the N-terminus. There are five canonical Notch ligands i.e. Jagged (JAG1 and JAG2), Delta-like (DLL1, DLL3, DLL4) in mammals. Notch signaling activation occurs upon ligand-receptor binding, which are expressed on two adjacent cells. Ligand binding causes dissociation of NEC from NTM, unmasking the ADAM cleavage site. The NEC fragment is trans- endocytosed into the ligand expressing cells. The full-length receptor minus the NEC fragment is cleaved at the membrane by ADAM17 generating an intermediate, Notch extracellular truncation (NEXT). This is further cleaved by γ-secretase that generates an active Notch intracellular fragment (NIC) or Notch intracellular domain (NICD). The γ-secretase complex is composed of PSEN1, PSEN2, PSENEN, NCSTN and APH1 (A or B). Following these two cleavage steps, the NICD is released into the cytoplasm and translocates into the nucleus to regulate transcription of Notch target genes. Upon translocation into the nucleus, NICD binds to RBPJ which is a constitutive repressor of Notch signaling. RBPJ represses Notch target gene expression by recruiting a co-repressor complex, which includes NCOR1, NCOR2, SNW1, CIR, HDAC1, HDAC2, SPEN and FHL1 and SAP30. NICD binding to RBPJ replaces the co-repressor complex with a co-activator complex which includes MAML1-3, EP300 and SNW1. Primary Notch target genes include two families of transcriptional factors Hes, including HES1 and HES5 as well as Hey including HEY1 and HEY2. Other Notch target genes include CCND1, CDKN1A, GATA3 and PTCRA. CNTN1 acts as a functional ligand of Notch. This trans-extracellular interaction causes γ-secretase-dependent nuclear translocation of the NICD. This signaling is involved in oligodendrocyte precursor cell differentiation and upregulation of myelin-related protein MAG. In addition to the canonical Notch pathway, there is increasing evidence showing RBPJ independent non-canonical pathways. been fully characterized. Physical interaction of NOTCH-1IC with LCK- PI3K may mediate non-nuclear cross-talk with AKT, leading to survival signaling. Notch stimulation through AKT pathway leads to down regulation of MYC expression. Activation of SRC/STAT3 pathway by Notch signaling is dependent on the expression of Notch effector HES1 transcription factor. The induction of HES1 enhanced SRC phosphorylation. This activated SRC kinase was found to be responsible for the enhanced phosphorylation of STAT3. The HES1 and HES5 proteins associate with and facilitate the complex formation between JAK2 and STAT3, thus promoting STAT3 phosphorylation and activation. The activated STAT3 translocates from the cytoplasm to the nucleus and induces transcriptional activation of target gene expression (including HIF1A). Please access this pathway at [http://www.netpath.org/netslim/notch_pathway.html NetSlim] database. If you use this pathway, please cite following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. <i>Genome Biology</i>. 11:R3.

notch 信号通路作为一种在进化过程中得以保守的信号传导途径，在众多发育和生理过程中扮演着至关重要的角色。这些过程涵盖了细胞命运决定、组织形态构建和形态发生、细胞分化、增殖以及细胞凋亡等方面。此通路得名于在果蝇突变体中，昆虫翅膀尖端缺失组织区域出现的非正常缺口。Notch 基因于 1985 年被克隆。Notch 家族蛋白为单跨膜蛋白，兼具细胞表面受体和细胞核转录调控因子的功能。哺乳动物中已鉴定出四种 Notch 受体（Notch 1-4）。成熟的 Notch 受体由非共价异二聚体构成，包括细胞外亚基（NEC）和跨膜亚基（NTM）。NEC 含有多个表皮生长因子样重复序列和三个特化的 Lin-Notch 重复序列（LNR），这些序列与 NTM 的细胞外末端形成紧密的疏水相互作用。这一区域掩盖了一个天冬氨酸蛋白酶和金属蛋白酶（ADAM）的切割位点。这两个亚基相互作用区域被称为异二聚化域（HD）。Notch 配体也是跨膜蛋白，含有多个表皮生长因子样重复序列、短细胞质尾部以及位于 N 端的特化 delta-serrate-lag2（DSL）结构域。哺乳动物中有五种经典 Notch 配体，即 Jagged（JAG1 和 JAG2）和 Delta-like（DLL1、DLL3、DLL4）。Notch 信号通路的激活发生在配体与受体的结合之后，这种结合发生在相邻的两个细胞之间。配体结合导致 NEC 从 NTM 解离，暴露出 ADAM 切割位点。NEC 片段被跨膜内吞至配体表达细胞内。完整受体减去 NEC 片段后，在膜上被 ADAM17 蛋白切割，生成一个中间产物，即 Notch 细胞外截断（NEXT）。该中间产物随后被 γ-分泌酶进一步切割，生成一个具有活性的 Notch 细胞内片段（NIC）或 Notch 细胞内结构域（NICD）。γ-分泌酶复合体由 PSEN1、PSEN2、PSENEN、NCSTN 和 APH1（A 或 B）组成。经过这两次切割步骤后，NICD 被释放到细胞质中，并转位到细胞核中以调节 Notch 目标基因的转录。在转位到细胞核后，NICD 与组成型抑制因子 RBPJ 结合。RBPJ 通过募集包含 NCOR1、NCOR2、SNW1、CIR、HDAC1、HDAC2、SPEN 和 FHL1 以及 SAP30 的共抑制复合物来抑制 Notch 目标基因的表达。NICD 与 RBPJ 的结合将共抑制复合物替换为共激活复合物，该复合物包括 MAML1-3、EP300 和 SNW1。主要的 Notch 目标基因包括 Hes 家族转录因子，如 HES1 和 HES5，以及 Hey 家族，包括 HEY1 和 HEY2。其他 Notch 目标基因还包括 CCND1、CDKN1A、GATA3 和 PTCRA。CNTN1 作为 Notch 的功能性配体。这种跨细胞外相互作用导致 NICD 的 γ-分泌酶依赖性细胞核转位。这种信号传导参与少突胶质细胞前体细胞的分化和髓鞘相关蛋白 MAG 的上调。除了经典的 Notch 通路外，越来越多的证据表明存在 RBPJ 依赖的非常规通路。NOTCH-1IC 与 LCK-PI3K 的物理相互作用可能介导与 AKT 的非核跨通讯，从而引发生存信号。通过 AKT 通路进行的 Notch 刺激导致 MYC 表达的下调。Notch 信号激活 SRC/STAT3 通路依赖于 Notch 效应因子 HES1 转录因子的表达。HES1 的诱导增强了 SRC 的磷酸化。这种激活的 SRC 酪氨酸激酶被发现负责增强 STAT3 的磷酸化。HES1 和 HES5 蛋白与 JAK2 和 STAT3 结合并促进其复合物的形成，从而促进 STAT3 的磷酸化和激活。激活的 STAT3 从细胞质转位到细胞核，并诱导目标基因（包括 HIF1A）的转录激活。请访问 [http://www.netpath.org/netslim/notch_pathway.html NetSlim] 数据库以获取此通路信息。若使用此通路，请引用以下论文：Kandasamy, K. 等人（2010）. NetPath: 一个经过验证的信号传导通路公共资源。基因组生物学。11:R3。