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Published on: March 3, 2023
ROR1-CAVIN3 interaction required for caveolae-dependent endocytosis and pro-survival signaling in lung adenocarcinoma
Tomoya Yamaguchi1,2,3, Miyu Hayashi1, Lisa Ida1
1Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Abstract:
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transcriptional target of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinomas. In addition to its kinase-dependent role, ROR1 functions as a scaffold protein to facilitate interaction between caveolin-1 (CAV1) and CAVIN1, and consequently maintains caveolae formation, which in turn sustains pro-survival signaling toward AKT from multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET (proto-oncogene, receptor tyrosine kinase), and IGF-IR (insulin-like growth factor receptor 1). Therefore, ROR1 is an attractive target for overcoming EGFR-TKI resistance due to various mechanisms such as EGFR T790M double mutation and bypass signaling from other RTKs. Here, we report that ROR1 possesses a novel scaffold function indispensable for efficient caveolae-dependent endocytosis. CAVIN3 was found to bind with ROR1 at a site distinct from sites for CAV1 and CAVIN1, a novel function required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, but not caveolae formation itself. Furthermore, evidence of a mechanistic link between ROR1-CAVIN3 interaction and consequential caveolae trafficking, which was found to utilize a binding site distinct from those for ROR1 interactions with CAV1 and CAVIN1, with RTK-mediated pro-survival signaling towards AKT in early endosomes in lung adenocarcinoma cells was also obtained. The present findings warrant future study to enable development of novel therapeutic strategies for inhibiting the multifaceted scaffold functions of ROR1 in order to reduce the intolerable death toll from this devastating cancer.
Insights
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) acts as a scaffold protein, crucial for caveolae-dependent endocytosis and signaling in lung cancer. Targeting ROR1
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transcriptional target of NKX2-1/TTF-1 in lung adenocarcinomas.
- ROR1 acts as a scaffold protein, maintaining caveolae formation and supporting pro-survival signaling from receptor tyrosine kinases (RTKs) like EGFR, MET, and IGF-IR.
- ROR1 is a potential therapeutic target for overcoming resistance to EGFR-TKI treatments in lung cancer.
Purpose of the Study:
- To investigate the novel scaffold function of ROR1 in caveolae-dependent endocytosis.
- To elucidate the interaction between ROR1 and CAVIN3 and its role in cellular processes.
- To explore the mechanistic link between ROR1-CAVIN3 interaction, caveolae trafficking, and pro-survival signaling in lung adenocarcinoma.
Main Methods:
- Investigated ROR1's scaffold function beyond its role in caveolae formation.
- Characterized the binding interaction between ROR1 and CAVIN3.
- Examined the impact of ROR1-CAVIN3 interaction on subcellular localization, endocytosis, and signaling pathways in lung adenocarcinoma cells.
Main Results:
- ROR1 possesses a novel scaffold function essential for efficient caveolae-dependent endocytosis.
- CAVIN3 binds to ROR1 at a distinct site, facilitating CAVIN3 localization and caveolae-dependent endocytosis, but not caveolae formation.
- A mechanistic link was established between ROR1-CAVIN3 interaction, caveolae trafficking, and RTK-mediated pro-survival signaling towards AKT in early endosomes.
Conclusions:
- ROR1's multifaceted scaffold functions, particularly its role in caveolae-dependent endocytosis via CAVIN3 interaction, are critical in lung adenocarcinoma.
- Targeting ROR1's novel scaffold functions presents a promising therapeutic strategy to combat lung cancer.
- Further research into inhibiting ROR1's scaffold functions could lead to novel treatments for lung cancer.
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