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Fig. 6 | Cancer Cell International

Fig. 6

From: A novel Notch1 missense mutation (C1133Y) in the Abruptex domain exhibits enhanced proliferation and invasion in oral squamous cell carcinoma

Fig. 6

Schematic model for EGFR-PI3K/AKT signaling activation induced by Notch1C1133Y mutation. a Schematic depiction of Abruptex domain C1133Y mutation and S1-3 cleavages in Notch1 receptor protein. EGF epidermal growth factor, LNR Lin/Notch repeats, HD (N and C regions), heterodimerization domain, TM transmembrane domain, RAM RBP-Jκ-associated molecule region, ANK ankyrin repeats, TAD transactivation domain, PEST sequence rich in proline, glutamic acid, serine, and threonine. S1-3, S1-3 cleavages. Black arrows indicate the sites of the cleavages. Red arrow indicates the site of the C1133Y mutation. b Model for aberrant EGFR-PI3K/AKT signaling pathway activation by Notch1 C1133Y mutation. The Notch1 protein is synthesized in endoplasmic reticulum and is transported to Golgi complex for S1-cleavage. The S1-cleaved mature Notch1 protein is presented on cell surface, where it has an inhibitory effect on EGFR phosphorylation. The ligand binding causes cleavage of the receptor at the S2-cleavage site. The remaining Notch1 receptor undergoes further cleavage at the S3 site, freeing the NICD domain. The NICD translocates to the nucleus where it binds to the DNA-binding protein CSL and was recognized by the transcriptional coactivator Mastermind (MAM). The triprotein complex recruits additional coactivators (Co-A) to activate target genes. In this study, we find that the Notch1 signaling has an inhibitory effect on EGFR activation. When Notch1 C1133Y mutation occurs, Notch1 protein is arrested in endoplasmic reticulum and is unable to be transported to Golgi complex for S1-cleavage, thus the canonical Notch1 signaling activation is disrupted. The PI3K/AKT signaling is activated by Notch1 protein arrest in endoplasmic reticulum induced by Notch1 C1133Y mutation. Moreover, the loss of inhibitory effect by Notch1 loss-of-function mutation can also induces EGFR phosphorylation, thus activating PI3K/AKT signaling. NECD Notch1 extracellular domain, NICD Notch1 intracellular domain

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