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The Tetraspanin Tspan8 Associates with Endothelin Converting Enzyme ECE1 and Regulates Its Activity
Yingying Zhu1,2,3, Julien Saint-Pol1,4, Viet Nguyen2,5
1UMR-S 1004, SFR André Lwoff, Inserm, 94800 Villejuif, France.
Abstract:
Tspan8 is a member of the tetraspanins family of cell surface molecules. The ability of tetraspanins to organize membrane microdomains with other membrane molecules and interfere with their function suggests that they could act as surface integrators of external or internal signals. Among the first identified tetraspanins, Tspan8 promotes tumor progression and metastasis, presumably by stimulating angiogenesis and cell motility. In patients, its expression on digestive tract tumors seems to be associated with a bad prognosis. We showed previously that Tspan8 associates with E-cadherin and EGFR and modulates their effects on cell motility. Using Mass spectrometry and western blot, we found a new partner, the endothelin converting enzyme ECE1, and showed that Tspan8 amplifies its activity of conversion of the endothelin-1 precursor bigET1 to endothelin. This was observed by transduction of the colon carcinoma cell line Isreco1, which does not express Tspan8, and on ileum tissue fragments of tspan8ko mice versus wild type mice. Given these results, Tspan8 appears to be a modulator of the endothelin axis, which could possibly be targeted in case of over-activity of endothelins in biological processes of tissues expressing Tspan8.
Insights
Tetraspanin 8 (Tspan8) amplifies endothelin-1 production, impacting tumor progression. Targeting Tspan8 may offer a strategy for treating cancers with overactive endothelin signaling.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Tspan8 is a tetraspanin protein involved in cell signaling and tumor progression.
- Tetraspanins organize membrane microdomains, influencing cell surface molecule functions.
- Tspan8 expression correlates with poor prognosis in digestive tract tumors.
Purpose of the Study:
- To identify novel Tspan8 interaction partners.
- To investigate Tspan8's role in the endothelin signaling pathway.
- To explore Tspan8 as a potential therapeutic target in cancer.
Main Methods:
- Mass spectrometry and western blot to identify Tspan8 binding partners.
- Functional assays using Isreco1 colon carcinoma cell line (Tspan8-negative).
- Comparative analysis of ileum tissue from Tspan8 knockout (tspan8ko) and wild-type mice.
Main Results:
- Identified endothelin converting enzyme 1 (ECE1) as a novel Tspan8 binding partner.
- Demonstrated that Tspan8 amplifies ECE1's conversion of big endothelin-1 (bigET1) to endothelin-1.
- Observed enhanced endothelin axis activity in Tspan8-expressing cells and tissues.
Conclusions:
- Tspan8 acts as a modulator of the endothelin axis.
- Tspan8's amplification of endothelin-1 production contributes to its role in tumor progression.
- Targeting Tspan8 could be a therapeutic strategy for conditions involving endothelin pathway overactivity.
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