A Wnt-Independent LGR4–EGFR Signaling Axis in Cancer Metastasis
Abstract
Leucine-rich repeat-containing G protein–coupled receptors 4, 5, and 6 (LGR4/5/6) play critical roles in development and cancer. The widely accepted mechanism is that these proteins, together with their R-spondin ligands, stabilize Wnt receptors, thus potentiating Wnt signaling. Here we show that LGR4 enhanced breast cancer cell metastasis even when Wnt signaling was deactivated pharmacologically or genetically. Furthermore, LGR4 mutants that cannot potentiate Wnt signaling nevertheless promoted breast cancer cell migration and invasion in vitro and breast cancer metastasis in vivo. Multiomic screening identified EGFR as a crucial mediator of LGR4 activity in cancer progression. Mechanistically, LGR4 interacted with EGFR and blocked EGFR ubiquitination and degradation, resulting in persistent EGFR activation. Together, these data uncover a Wnt-independent LGR4–EGFR signaling axis with broad implications for cancer progression and targeted therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 07, 2021
- Source ID
- 10.1158/0008-5472.can-21-1112
Entities
People
- Adelaide Ij Young
- Amy T. Ku
- Chad J Creighton
- Chandandeep Nagi
- Cristian Coarfa
- Eric P. Souto
- Fei Yue
- Qingyun Liu
- Shixia Huang
- Susan Hilsenbeck
- Tao Wang
- Weijie Zhang
- Weiyu Jiang
- Xia Lin
- Xiang H-F Zhang
- Xin-Hua Feng
- Yankun Gao
- Yi Li
- Yi Wang
- Zihan Yu
Organizations
- Baylor College of Medicine
- National Institutes of Health
- Zhejiang University