A positive feedback loop between hepatocyte growth factor receptor and β-catenin sustains colorectal cancer cell invasive growth

Abstract

Overexpressed or activated hepatocyte growth factor receptor, encoded by the MET proto-oncogene, was found in the majority of colorectal carcinomas (CRCs), whose stepwise progression to malignancy requires transcriptional activation of b-catenin. We here demonstrate that a functional crosstalk between Met and b-catenin signaling sustains and increases CRC cell invasive properties. Hepatocyte growth factor (HGF) stimulation prompts b-catenin tyrosine phosphorylation and dissociation from Met, and upregulates b-catenin expression via the phosphatidylinositol 3-kinase pathway in conditions that mimic those found by the invading and metastasizing cells. Additionally, a transcriptionally active form of b-catenin, known to be oncogenic, enhances Met expression. Furthermore, HGF treatment increases the activity of the b-catenin-regulated T-cell factor transcription factor in cells expressing the wild-type or the oncogenic b-catenin. In the mirror experiments, either Met or b-catenin knocking down also reduces their protein level. In biological assays, b-catenin knocking down abrogates the HGF-induced motile phenotype, whereas active b-catenin fosters ligand-independent cell scattering. Met and b-catenin also cooperate in promoting entry into the cell cycle and in protecting cells from apoptosis. In conclusion, Met and b-catenin pathways are mutually activated in CRC cells. This might generate a selfamplifying positive feedback loop resulting in the upregulation of the invasive growth properties of CRC cells.

Hypothermia blocks β-catenin degradation after focal ischemia in rats

“…Nevertheless, it is yet not clear how hypothermia retarded β-catenin's degradation. As we have discussed, in the penumbra of normothermic brain, transient increases in β-catenin phosphorylation at 5h appear to correlate with β-catenin degradation at later time points, which is consistent with the notion that β-catenin phosphorylation results its degradation [9,11]. However, in the penumbra of hypothermic brains, phosphorylated β-catenin accumulated from 5 to 48 h after stroke while total β-catenin was not degraded, which contradicts the aforementioned hypothesis.…”

“…We found in this study that β-catenin phosphorylation transiently increased at 5h in the normothermic brain, and this hyper-phosphorylation was accompanied by a later degradation of total β-catenin. This correlation suggests that β-catenin phosphorylation progresses to degradation [9,11]. Furthermore, β-catenin might be phosphorylated by GSK3 β activity, as levels of phosphorylated GSK3 β transiently decreased from 5h to 24h, indicating increasedactivity during this period after stroke.…”

“…Activated GSK 3 β, on the other hand, phosphorylates β-catenin, resulting its proteosomal degradation [13]. Stabilized β-catenin translocates into the nuclei, activating gene expression that supports cell survival [9,11]. β-catenin has been shown to decrease in brains of patients with Alzheimer's disease [5].…”

Induction and Down-regulation of Sox17 and Its Possible Roles During the Course of Gastrointestinal Tumorigenesis

“…It has also been shown that β-catenin accumulation, a hallmark of Wnt activation, is particularly enhanced in the invasion front and metastasized colon cancer cells, suggesting that promotion of Wnt/β-catenin signaling is important for malignant progression 8 . Growth factors PDGF and HGF, as well as inflammatory cytokine TNF-α, have been shown to promote Wnt/β-catenin signaling activity in tumor cells [9][10][11] .…”

A novel positive feedback loop involving FASN/p-ERK1/2/5-LOX/LTB4/FASN sustains high growth of breast cancer cells

“…In the network of signaling transduction, the positive feedback loop regulation plays important roles in determining the progressive nature of malignant cancer cells including cell proliferation [2][3][4][5] . Extracellular signal-regulated kinase 1/2 (ERK1/2), a major cellular proliferation signaling pathway, is involved in many positive feedback loops.…”