Impaired membrane-type 1 matrix metalloproteinase phosphorylation results in blocking 3D-collagen invasion by tumor cells through cell cycle arrest in G0/G1 phase
Bibliographic record
Abstract
B200 Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a transmembrane matrix metalloproteinase (MMP) that degrades several component of the extracellular matrix, and this activity has been shown to be important for both tumor growth and invasion. We have recently shown that MT1-MMP is phosphorylated on its unique cytoplasmic tyrosine 573, and that this phosphorylation is necessary for in vitro tumor cell migration. In this study, we investigate the mechanisms involved in phosphoMT1-MMP- mediated tumor cell proliferation and invasion. Fibrosarcoma cells (HT-1080) were stably transfected with the wild type or the non-phosphorylable (Y573F mutant) forms of MT1-MMP. Cell proliferation and invasion studies were performed on 2D- or within a 3D-type 1 collagen matrix. MT1-MMP expression was determined by reverse transcription PCR, western blot or zymography. Cell cycle was analysed by flow cytometry. Flow cytometry analysis of the stable transfectants showed that MT1-MMP was expressed at the cell surface of both the Y573F mutant- or the wild type- expressing HT-1080 cells, the two forms of the enzyme being catalytically active, as monitored by zymography. Although both the wild type- and the Y573F-expressing HT-1080 cells had the same proliferation rate on 2D-type 1 collagen matrix, we observed that HT-1080 cells stably expressing the Y573F mutant form of MT1-MMP grew less within a 3D-type 1 collagen matrix than the cells expressing the wild type form of MT1-MMP. Similar results were observed when cells were allowed to invade a 3D-type 1 collagen matrix. Such an inhibition of both cell growth and invasion in 3D-type 1 collagen was correlated with alteration of the cell cycle. Indeed, flow cytometry analysis show that most of the Y573F mutant expressing HT-1080 cells were arrested in G0/G1 cell cycle phase, while cells expressing the wild type form of MT1-MMP were predominantly in the G2/M phase. These results thus suggest that phosphorylation of MT1-MMP may play an important role in tumour cell proliferation and invasion through cell cycle regulation. Given that pharmacological inhibition of MMP catalytic activities has been shown to induce several undesirable side effects, these findings suggest that the inhibition of MT1-MMP tyrosine phosphorylation may represent an unexpected alternative strategy for the development of drugs aimed at the inhibition of tumor invasion and metastasis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".