| First Author | Gao C | Year | 2024 |
| Journal | Elife | Volume | 13 |
| PubMed ID | 38921956 | Mgi Jnum | J:352253 |
| Mgi Id | MGI:7705613 | Doi | 10.7554/eLife.94605 |
| Citation | Gao C, et al. (2024) FAK loss reduces BRAF(V600E)-induced ERK phosphorylation to promote intestinal stemness and cecal tumor formation. Elife 13 |
| abstractText | BRAF(V600E) mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF(V600E) drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in BRAF(V600E)-mutant adenomas/polyps in mice and patients. In Vil1-Cre;BRAF(LSL-V600E/+);Ptk2(fl/fl) mice, Fak deletion maximized BRAF(V600E)'s oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAF(V600E)-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for BRAF(V600E)-induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation. |
