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RAL GTPases mediate EGFR-driven intestinal stem cell proliferation and tumourigenesis
Máté Nászai1,2, Karen Bellec1,2, Yachuan Yu1,2,3
1Wolfson Wohl Cancer Research Centre, Glasgow, United Kingdom.
Elife
|June 7, 2021
Summary
RAS-like (RAL) GTPases are crucial for activating EGFR/MAPK signaling in the intestine, impacting stem cell regeneration and tumor growth. Their role in adult tissue homeostasis and malignant transformation is newly uncovered.
Area of Science:
- Cell Biology
- Molecular Biology
- Gastroenterology
Background:
- RAS-like (RAL) GTPases are involved in Wnt signaling, affecting intestinal stem cell proliferation and regeneration.
- The precise role of RAL proteins as canonical RAS effectors in the intestine and their contribution to tumorigenesis are not fully understood.
Purpose of the Study:
- To elucidate the function of RAL GTPases in intestinal stem cell biology and their role in tumorigenesis.
- To investigate the mechanisms by which RAL GTPases regulate EGFR/MAPK signaling in the intestine.
Main Methods:
- Utilized Drosophila models to study RAL GTPase function in intestinal stem and progenitor cells.
- Investigated the effects of RalA knockdown on EGFR localization and MAPK pathway activation.
- Examined the impact of RAL GTPases on intestinal regeneration and EGFR-dependent tumor growth.
Main Results:
- RAL GTPases are necessary and sufficient to activate EGFR/MAPK signaling in the intestine by inducing EGFR internalization.
- Knockdown of Drosophila RalA increased plasma membrane-associated EGFR and decreased MAPK pathway activation.
- RAL GTPases influence stem cell proliferation during regeneration and contribute to EGFR-dependent tumorigenic growth in both intestinal and human mammary epithelium.
Conclusions:
- RAL GTPases are essential mediators of adult tissue homeostasis and malignant transformation in the intestine.
- The function of RAL GTPases in the intestine is distinct from the effects of oncogenic RAS.
- These findings reveal novel cellular and molecular contexts for RAL GTPase function in health and disease.
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