Presenilin modulates EGFR signaling and cell transformation by regulating the ubiquitin ligase Fbw7

Abstract

The epidermal growth factor receptor (EGFR) and Notch signaling pathways have antagonistic roles during epidermal differentiation and carcinogenesis. The molecular mechanisms regulating the crosstalk between EGFR and Notch during epidermal transformation are largely unknown. We found enhanced EGFR-dependent signaling, proliferation and oncogenic transformation caused by loss of presenilins (PS), the catalytic components of γ-secretase that generates the Notch1 intracellular domain (NICD). The underlying mechanism for abnormal EGFR signaling in PS-deficient cells involves γ-secretase-independent transcriptional upregulation of the E3 ubiquitin ligase Fbw7. Fbw7α, which targets NICD for degradation, regulates positively EGFR by affecting a proteasome-dependent ubiquitination step essential for constitutive degradation and stability of EGFR. To investigate the pathological relevance of this findings in vivo, we generated a novel epidermal conditional PS-deficient (ePS cDKO) mouse by deleting both PS in keratinocytes of the basal layer of the epidermis. The ePS cDKO mice develop epidermal hyperplasia associated with enhanced expression of both EGFR and Fbw7 and reduced NICD levels in keratinocytes. These findings establish a novel role for PS on epidermal growth and transformation by reciprocally regulating the EGFR and Notch signaling pathways through Fbw7.

Study of single nucleotide polymorphisms of FBW7 and its substrate genes revealed a predictive factor for paclitaxel plus cisplatin chemotherapy in Chinese patients with advanced esophageal squamous cell carcinoma

“…Similar results were also observed in ovarian cancer cell lines with naturally occurring F-box and WD repeat domain-containing 7 (FBW7) mutations [10]. It has been determined that the specific substrates of FBW7 consist of cyclin E [11,12], c-Myc [13,14], c-Jun [15,16], Notch [16–18], presenilin [19], Mcl-1 [20], sterol regulatory element-binding proteins (SREBP) [21,22], mTOR [23], Kruppel-like factors (KLFs) [24,25], c-Myb [26], and Aurora A [27]. Proteins encoded by different SNPs of these FBW7 substrate genes are frequently overexpressed in a variety of human cancers.…”

Differential regulation of FBXW7 isoforms by various stress stimuli

“…25 The α isoform is indirectly repressed by Presenilin 23 and directly by C/EBPδ 24 . Fbxw7 expression is also repressed by microRNAs such as miR-27 27 and miR-223.…”

“…Handfuls of factors have been suggested to regulate FBXW7 expression. p53 upregulates FBXW7β, 20,21 but was also suggested to affect FBXW7α expression, 22 whereas presenilin, 23 C/EBPδ, 24 Hes5, 25 and the 2 microRNAs miR223 and miR27a 26,27 might repress FBXW7 isoforms. In this paper, we further addressed the issue of isoform expression by monitoring the abundance of the mRNA of each FBXW7 isoform during the cell cycle and after exposure of cells to various stress stimuli with special emphasis on the role of p53 in the regulation of FBXW7β during stress responses.…”

Role of the ubiquitin ligase Fbw7 in cancer progression

“…It has been reported that Fbw7α targets Notch1 intracellular domain (NICD) for degradation, positively regulates epidermal growth factor receptor (EGFR) by affecting ubiquitylation and stability of EGFR. In the meantime, PS negatively modulates Fbw7 transcription, thus positively and negatively regulates EGFR and Notch signaling, respectively [41]. Using a novel epidermal conditional PSdeficient mouse model deleting PS in keratinocytes of the basal layer of the epidermis, researchers found the mice developed epidermal hyperplasia associated with increased expression of both EGFR and Fbw7 and reduced NICD level in keratinocytes.…”