Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-ALL

The two subunits of the mature NOTCH1 receptor are generated by cleavage by a furin protease in the trans-Golgi network soon after translation of NOTCH1 precursor protein. The extracellular subunit responsible for ligand-receptor interaction and the transmembrane subunit responsible for triggering transcription activation interact by their respective heterodimerization (HD) domains. Upon binding to its ligands –Delta-like 1, 3 and 4; Jagged 1 and 2– the transmembrane portion of NOTCH1 is sequentially cleaved by ADAM proteases and then by the γ-secretase complex. This final proteolytic cleavage liberates the active intracellular fragment of NOTCH1 (ICN1), which translocates to the nucleus and activates the expression of target genes by forming a ternary complex with the CSL DNA binding protein and the MAML1 transcriptional coactivator. Small molecule inhibitors of the γ-secretase block NOTCH1 activation by retaining the receptor at the membrane. NOTCH1 promotes cell growth by transcriptional upregulation of genes involved in anabolic pathways and also by transcriptional upregulation of MYC. In addition NOTCH1 induces the expression of HES1, a transcriptional repressor that promotes the upregulation of the PI3K-AKT signaling pathway by transcriptional downregulation of PTEN. Termination of NOTCH1 signaling is mediated by phosphorylated-coupled degradation of the activated receptor in the proteasome via FBXW7-SCF.

Publication

Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-ALL. () Teresa Palomero, et al. Clin Cancer Res. ;14(17):5314-5317. Figure: F1. All organisms Mus musculus Drosophila melanogaster Homo sapiens Danio rerio

Disease mentions