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1.
Figure 1

Figure 1. Canonical and non-canonical Notch signaling in mammals. From: Alteration of Notch signaling in skeletal development and disease.

In the canonical pathway, binding between transmembrane Notch receptors and its ligands triggers ADAM10- and Presenilin-mediated proteolytic cleavage. This liberates the membrane-bound Notch intracellular domain (NICD) to translocate into the nucleus, where NICD forms a transcriptional complex with nuclear factor RBPJ and the co-activator MAML to regulate transcription of downstream genes, such as HES1 and HEY1, the two classic targets of Notch. The non-canonical pathway or RBPJ-independent Notch signaling occurs in Drosophila and mammals. Here, Notch can activate integrin via the membrane associated small GTPase R-Ras independent of binding RBPJ. In addition, NICD can interact with IKK╬▒ in the NF-kB pathway or LEF1 in the Wnt pathway.

Jianning Tao, et al. Ann N Y Acad Sci. ;1192:257-268.
2.
Figure 2

Figure 2. Cell autonomous and non-cell autonomous functions of Notch in osteoblasts. From: Alteration of Notch signaling in skeletal development and disease.

Notch regulates osteoblast differentiation through two different mechanisms: (1) to promote the self-renewal of MSC and the proliferation of pre-osteoblast and immature osteoblasts; (2) to inhibit the differentiation from MSC to pre-osteoblast or from immature to mature osteoblast. Osteosarcoma cells have a high level expression of Notch indicating pathological gain-of- function of Notch may contribute to tumorigenesis of bone cells. The de-differentiation of fibroblast into pluripotent progenitors opens the possibility that de-differentiation of mature osteoblasts may lead to a cancer stem cells or OS (dash line). Notch signaling in osteoblast not only regulates osteoblast function in cell autonomous fashion, but also influences other cell types which directly and indirectly interact with osteoblasts within bone marrow. Notch regulates expression of Osteoprotegerin (OPG), an important factor for inhibiting osteoclast differentiation. Similarly, osteoblastic cells may modulate activities of the hematopoietic stem cell (HSC) or HSC-derived cells through unknown factors in a Notch-dependent, non-cell autonomous manner.

Jianning Tao, et al. Ann N Y Acad Sci. ;1192:257-268.

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