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Updated: Jun 25, 2025
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
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Inhibiting HSD17B8 suppresses the cell proliferation caused by PTEN failure.
Wei Zhao1,2, Ruiting Huang1, Dongyang Ran1
1School of Basic Medical Sciences, Henan University, Kaifeng, Henan Province, China.
Scientific Reports
|May 29, 2024
Summary
The tumor suppressor PTEN (phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase) interacts with HSD17B8, regulating cell division independently of PTEN
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- The tumor suppressor PTEN homolog daf-18 in C. elegans regulates cell division during L1 arrest.
- Established pathways involving PTEN's phosphatase activity are well-studied.
- A novel mechanism for PTEN-mediated cell cycle control is investigated.
Purpose of the Study:
- To identify novel regulators of cell proliferation controlled by daf-18.
- To elucidate the mechanism by which PTEN modulates cell division independently of its phosphatase activity.
- To explore a new protein-protein interaction involving PTEN in tumor suppression.
Main Methods:
- Forward genetic screening in Caenorhabditis elegans (C. elegans).
- Identification and characterization of the F12E12.11 gene and its protein product.
- Analysis of protein-protein interactions between daf-18 and F12E12.11.
- Investigation of the enzymatic activity of F12E12.11 (HSD17B8) and its effect on steroid hormone levels.
- Cell cycle analysis and pathway investigation (MAPK/ERK).
Main Results:
- A novel gene, F12E12.11, was identified as being regulated by daf-18 and impacting cell proliferation.
- F12E12.11 is the C. elegans ortholog of human estradiol 17-beta-dehydrogenase 8 (HSD17B8).
- PTEN physically interacts with HSD17B8, modulating its activity.
- This interaction leads to reduced estrone and increased estradiol levels.
- Estradiol accumulation may arrest tumor cells in G2/M phase via MAPK/ERK signaling.
Conclusions:
- PTEN restrains cell division through an unconventional interaction with HSD17B8, independent of its phosphatase activity.
- This interaction provides a novel mechanism for PTEN-mediated tumor suppression.
- The findings reveal intricate molecular interactions governing cell cycle control and tumor suppression.
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