The mechanism of NOTCH2NL-mediated regulation of NOTCH signa...

created [InstanceEdit:9911721] Orlic-Milacic, Marija, 2024-06-05
dbId 9911719
displayName The mechanism of NOTCH2NL-mediated regulation of NOTCH signa...
literatureReference
modified [InstanceEdit:9919314] Matthews, Lisa, 2024-08-21
schemaClass Summation
text The mechanism of NOTCH2NL-mediated regulation of NOTCH signaling has not been fully elucidated. Two studies have shown that NOTCHNLs stimulate NOTCH signaling (Fiddes et al. 2018, Suzuki et al. 2018), while one study has reported that NOTCH2NLA inhibits NOTCH signaling (Duan et al. 2004). NOTCH2NLB was reported to co-immunoprecipitate with DLL1, a NOTCH ligand previously shown to be involved in cortical neurogenesis, and to decrease the availability of DLL1 for binding NOTCH (Suzuki et al. 2018). The interaction between NOTCH2NLs and DLL/JAG ligands is supported by structural properties of NOTCH2NLs, namely their NOTCH2-derived EGF repeats, knowing that EGF repeats enable the interaction between NOTCH receptors and DLL/JAG ligands. The interaction between DLL/JAG ligands and NOTCH receptors activates NOTCH signaling when it occurs in trans (when interacting DLL/JAG ligands and NOTCH receptors are expressed on the surface of neighboring cells), and inhibits NOTCH signaling when it occurs in cis (when interacting DLL/JAG ligands and NOTCH receptors are expressed on the surface of the same cell) (Cordle et al. 2008, Sprinzak et al. 2010). In cis (cell autonomously), Dll1 expression is known to promote neuronal fate and decrease self-renewal of neuronal progenitors in the mouse cortex (Kawaguchi et al. 2008). Dll1 overexpression leads to a decreased proportion of progenitor cells in the ventricular zone with a corresponding increase in neurons in the cortical plate in the developing mouse cortex, which is completely blocked by NOTCH2NLB co-expression, demonstrating that NOTCH2NLB directly inhibits DLL1 function in cis (Suzuki et al. 2018). Co-transfection of NOTCH2NLA and NOTCH2NLB expression constructs with NOTCH1-, NOTCH2-, or NOTCH3-GAL4 reporters (NOTCH4 was not tested in this context) increases reporter activity, both in the absence and presence of JAG2, DLL1, or DLL4 ligands (JAG1 was not tested in this context), suggesting the NOTCH2NLs positively regulate NOTCH signaling (Fiddes et al. 2018), and that NOTCH2NLs can likely bind other DLL/JAG ligands besides DLL1. NOTCH2NLB is more potent than NOTCH2NLA in the activation of the NOTCH2-GAL4 reporter in the presence of the JAG2 ligand (Fiddes et al. 2018). Overexpression of NOTCH1 intracellular domain (NICD1) in hESC-derived cortical progenitors has a similar effect as NOTCH2NLB overexpression (Suzuki et al. 2018), and both overexpressed NICD1 and overexpressed NOTCH2NLB lead to upregulation of the NOTCH target gene HES1 (Suzuki et al. 2018).

In contradiction to these recent reports, and earlier study reported that the co-expression of NOTCH2NLA with either NOTCH1 or NOTCH2 in HeLa cells repressed their transcriptional activity measured by the expression of a luciferase reporter under the control of the promoter of the NOTCH target gene HES1 (Duan et al. 2004).

NOTCH2NLs may also regulate NOTCH signaling by directly interacting with NOTCH receptors through EGF repeats. In vitro, recombinant NOTCH2NLB co-immunoprecipitates with recombinant NOTCH2 and vice versa (Fiddes et al. 2018).

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