Lysophosphatidic acid-induced transactivation of the EGF receptor regulates connexin43-mediated gap junctional communication in ovarian surface epithelial cells.
Bibliographic record
Abstract
174 Lysophosphatidic acid (LPA) is released by activated platelets and induces disruption of connexin43 (Cx43)-mediated cell-to-cell communication and enhanced cell proliferation in wound repair. The identification of LPA-activated mediators that regulate the growth-suppressive function of the Cx43 gap junction protein in normal ovarian cells may provide some insight into the development of ovarian cancer. These studies measured gap junctional communication (GJC) in rat ovarian surface epithelial (ROSE) cells by microinjecting a fluorescent dye into single cells and counting the neighboring cells that became fluorescent by dye transfer. Changes in Cx43 phosphorylation were detected by migration differences on SDS-PAGE and activation of protein kinases was demonstrated by Western blotting with phospho-specific antibodies or by immune complex activity assays. LPA induced a dose- and time-dependent fall in GJC in ROSE cells. Pre-treatment with pertussis toxin or a MEK inhibitor (PD98059) blocked the fall in GJC and the increase in Cx43 phosphorylation, supporting a role for a Gi G protein-coupled receptor (GPCR) and Erk kinases in these effects. Pretreatment with the Src family kinase inhibitor PP2 attenuated the fall in GJC and the increased Cx43 phosphorylation. Gi-GPCRs induce c-Src and Erk activation through transactivation of a receptor tyrosine kinase. We pretreated ROSE cells with an EGF receptor (EGFR) inhibitor (PD153035) to examine the role for the EGFR in LPA-induced signaling. Inhibiting the EGFR blocked LPA-induced auto-phosphorylation of the receptor, reduced the extent of Cx43 phosphorylation and prevented the fall in GJC. A recent study by Cameron et al. (JBC 2003) suggested that Erk5 is more important than Erk1/2 in the regulation of GJC in EGF-treated cells. We found that pre-treating ROSE cells with pertussis toxin, MEK inhibitor, PP2 or the EGFR inhibitor prevented the downstream activation of Erk5 in LPA-treated cells. In cells treated with the EGFR inhibitor and then with LPA, Erk1/2 was activated but GJC did not fall. These studies demonstrated that LPA induced Cx43 phosphorylation and disruption of GJC though a Gi-GPCR-dependent signaling pathway that initiated transactivation of the EGFR and activated an Src family kinase and Erk kinases. Importantly, transactivation of the EGFR was required for Erk5 activation and Erk5 was key for the fall in GJC. Since LPA disrupts Cx43-mediated GJC and the down regulation of Cx43 enhances cell proliferation, it is plausible that deregulation of LPA-activated signaling may down regulate the growth-suppressive function of Cx43 in normal ovarian surface epithelial cells and allow proliferation of abnormal cells that arise during the proliferative cycles of wound repair associated with ovulation and thus contribute to the development of ovarian cancer.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".