The NOTCH signaling pathway in normal and malignant blood cell production

Abstract

The NOTCH pathway is an evolutionarily conserved signalling network, which is fundamental in regulating developmental processes in invertebrates and vertebrates (Gazave et al. in BMC Evol Biol 9:249, 2009). It regulates self-renewal (Butler et al. in Cell Stem Cell 6:251-264, 2010), differentiation (Auderset et al. in Curr Top Microbiol Immunol 360:115-134, 2012), proliferation (VanDussen et al. in Development 139:488-497, 2012) and apoptosis (Cao et al. in APMIS 120:441-450, 2012) of diverse cell types at various stages of their development. NOTCH signalling governs cell-cell interactions and the outcome of such responses is highly context specific. This makes it impossible to generalize about NOTCH functions as it stimulates survival and differentiation of certain cell types, whereas inhibiting these processes in others (Meier-Stiegen et al. in PLoS One 5:e11481, 2010). NOTCH was first identified in 1914 in Drosophila and was named after the indentations (notches) present in the wings of the mutant flies (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010). Homologs of NOTCH in vertebrates were initially identified in Xenopus (Coffman et al. in Science 249:1438-1441, 1990) and in humans NOTCH was first identified in T-Acute Lymphoblastic Leukaemia (T-ALL) (Ellisen et al. in Cell 66:649-61, 1991). NOTCH signalling is integral in neurogenesis (Mead and Yutzey in Dev Dyn 241:376-389, 2012), myogenesis (Schuster-Gossler et al. in Proc Natl Acad Sci U S A 104:537-542, 2007), haematopoiesis (Bigas et al. in Int J Dev Biol 54:1175-1188, 2010), oogenesis (Xu and Gridley in Genet Res Int 2012:648207, 2012), differentiation of intestinal cells (Okamoto et al. in Am J Physiol Gastrointest Liver Physiol 296:G23-35, 2009) and pancreatic cells (Apelqvist et al. in Nature 400:877-881, 1999). The current review will focus on NOTCH signalling in normal and malignant blood cell production or haematopoiesis.

Fig. 1

NOTCH receptors. The mammalian NOTCH family has four members NOTCH1-4; all consist of extracellular and intracellular domains. The extracellular domain 29–36 Epidermal growth factor (EGF) like repeats followed by three Lin-NOTCH repeats (LNR). The intracellular domain has the RBP-J-associated molecule (RAM) domain, six ankyrin repeats (ANK), nuclear localization sequences (NLS), a transactivation domain (TAD) required for activating transcription and a proline-, glutamate-, serine- and threonine-rich (PEST) domain which regulates NOTCH degradation. NOTCH1 and NOTCH2 are structurally similar, NOTCH3 and NOTCH4 are smaller proteins as they have fewer EGF repeats and lack TAD

Fig. 2

NOTCH signaling pathway. In the golgi apparatus the Notch receptor undergoes proteolytic processing, which is S1 cleavage mediated by Furin proteases. The receptor is transported to the cell surface membrane. The extracellular domain of the Notch receptor (Notch-ECD) in the signalling cell binds with the Notch ligands (Delta, Jagged, Serrate) expressed by the adjacent cell. This induces the second proteolytic step, S2 cleavage by ADAM metalloproteases, and leads to the endocytosis of the Notch-ECD into the ligand-expressing cell. This is followed by the release of the Notch intracellular domain (Notch-ICD) with a tethered membrane. This is now a substrate for the gamma secretase enzyme complex, which cleaves the Notch-ICD from the membrane by S3 and S4 cleavages. The resulting active Notch-ICD translocates to the nucleus and interacts with the CSL protein. In the absence of Notch-ICD, the CSL is bound to co-repressor. Binding of Notch-ICD with CSL results in the formation of an active complex with MAML and other co-activators and leads to the transcription of Notch targets HES and HEY

Fig. 3

Haematopoiesis. Blood cell production is maintained by a small population of stem cells found in the bone marrow; these cells have the ability to self-renew or differentiate. Cells then differentiate to multi-potential and lineage committed progenitors; these cells can’t be distinguished morphologically, only by the use of clonogenic assays. The final stage of differentiation is when the cells develop their characteristic morphology and are released into the circulation