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Updated: Aug 10, 2025
Fluorescence-Based Measurements of Phosphatidylserine/Phosphatidylinositol 4-Phosphate Exchange Between Membranes
Published on: March 14, 2021
Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine
Paulina Urriola-Muñoz1, Luke A Pattison1, Ewan St J Smith1
1Department of Pharmacology, University of Cambridge, Cambridge, UK.
Abstract:
The naked mole-rat (NMR, Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that mature ADAM10 is expressed in NMR primary skin fibroblasts (NPSF), and that ionomycin increases cell surface ADAM10 localization. However, we observed an absence of ADAM10 mediated CD44 cleavage, as well as shedding of exogenous and overexpressed betacellulin in NPSF, whereas in mouse primary skin fibroblasts ionomycin induced ADAM10-dependent cleavage of both CD44 and betacellulin. Overexpressing a hyperactive form of the Ca2+ -dependent phospholipid scramblase ANO6 in NPSF increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted cell migration in NPSF in an ADAM10-dependent manner. These findings suggest that dysregulation of ADAM10 shedding activity is due to a deficient PS externalization in NMR.
Insights
Naked mole-rats resist cancer due to deficient phosphatidylserine externalization, which impairs ADAM10 sheddase activity. Restoring this process in skin cells promotes migration, suggesting a novel aging and cancer research avenue.
Area of Science:
- Biogerontology
- Cancer Research
- Cell Biology
Background:
- Naked mole-rats (NMRs) exhibit remarkable resistance to age-associated diseases, including cancer.
- CD44, a transmembrane glycoprotein, is implicated in cancer progression and its cleavage by ADAM10 regulates cell migration.
- ADAM10 activity is crucial for shedding cell surface proteins, influencing cellular processes.
Purpose of the Study:
- To investigate the function of ADAM10 and its role in CD44 cleavage in naked mole-rat primary skin fibroblasts (NPSF).
- To explore the mechanism behind the observed lack of ADAM10-mediated shedding in NPSF.
- To determine if restoring phosphatidylserine (PS) externalization can rescue ADAM10 sheddase activity and promote cell migration in NMRs.
Main Methods:
- Primary skin fibroblasts from naked mole-rats (NPSF) and mice were cultured.
- Ionomycin was used to stimulate cell surface ADAM10 localization and activity.
- Betacellulin shedding and CD44 cleavage were assessed.
- The calcium-dependent phospholipid scramblase ANO6 was overexpressed in NPSF to induce phosphatidylserine externalization.
- Cell migration assays were performed.
Main Results:
- Mature ADAM10 was expressed in NPSF, and ionomycin increased its cell surface localization.
- ADAM10-mediated cleavage of CD44 and shedding of betacellulin were absent in NPSF, unlike in mouse fibroblasts.
- Overexpression of a hyperactive ANO6 in NPSF rescued ADAM10 sheddase activity and promoted cell migration.
- This rescue of sheddase activity and promotion of cell migration were ADAM10-dependent.
Conclusions:
- Naked mole-rats exhibit deficient ADAM10 sheddase activity, linked to impaired phosphatidylserine externalization.
- Restoring phosphatidylserine externalization in NMR skin cells can rescue ADAM10 function and enhance cell migration.
- These findings offer insights into the unique aging and cancer resistance mechanisms of naked mole-rats.
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