Abstract
The Notch receptor is an evolutionarily highly conserved transmembrane protein essential to a wide spectrum of cellular systems, and its deregulation has been linked to a vast number of developmental disorders and malignancies. Regulated Notch function is critical for the generation of T-cells, in which abnormal Notch signaling results in leukemia. Notch activation through trans-activation of the receptor by one of its ligands expressed on adjacent cells has been well defined. In this canonical ligand-dependent pathway, Notch receptor undergoes conformational changes upon ligand engagement, stimulated by a pulling-force on the extracellular fragment of Notch that results from endocytosis of the receptor-bound ligand into the ligand-expressing cell. These conformational changes in the receptor allow for two consecutive proteolytic cleavage events to occur, which release the intracellular region of the receptor into the cytoplasm. It can then travel to the nucleus, where it induces gene transcription. However, there is accumulating evidence that other pathways may induce Notch signaling. A ligand-independent mechanism of Notch activation has been described in which receptor processing is initiated via cell-internal signals. These signals result in the internalization of Notch into endosomal compartments, where chemical changes existing in this microenvironment result in the conformational modifications required for receptor processing. This review will present mechanisms underlying both canonical ligand-dependent and non-canonical ligand-independent Notch activation pathways and discuss the latter in the context of Notch signaling in T-cells.
Highlights
The Notch receptors are evolutionarily highly conserved transmembrane proteins essential to a wide spectrum of cellular systems [1]
Blocking the endocytic pathway at later stages by deleting “endosomal sorting complexes required for transport proteins (ESCRT),” which control sorting into late endosomes (LE) (Figure 2), or Fab1 that is important in-lysosomal compartments, did not attenuate Notch signaling, but instead elevated it [75]
Deltex proteins are not required for thymic T-cell development [102], in which Notch activation is largely dependent on DLL4 [103], we hypothesize that in systems that utilize ligand-independent Notch activation, such as that initiated by TCR/CD28-mediated stimulation, Deltex, as well as many of the other proteins in the endocytic pathway discussed above, will be important players
Summary
The Notch receptors are evolutionarily highly conserved transmembrane proteins essential to a wide spectrum of cellular systems [1]. Blocking the endocytic pathway at later stages by deleting “endosomal sorting complexes required for transport proteins (ESCRT),” which control sorting into LE (Figure 2), or Fab that is important in (pre)-lysosomal compartments, did not attenuate Notch signaling, but instead elevated it [75] This enhanced signaling may be a result of prolonged retention of Notch in an environment where it can be processed by γSec. In mammalian cells, it was demonstrated that Notch is endocytosed during ligand-dependent activation [60]. Deltex proteins are not required for thymic T-cell development [102], in which Notch activation is largely dependent on DLL4 [103], we hypothesize that in systems that utilize ligand-independent Notch activation, such as that initiated by TCR/CD28-mediated stimulation, Deltex, as well as many of the other proteins in the endocytic pathway discussed above, will be important players. The acidic optimum for γSec activity may enable it to bypass S2 cleavage and directly process the 70aa-stub moiety of Notch [74]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
