ROR1 sustains caveolae and survival signalling as a scaffold of cavin-1 and caveolin-1.

Abstract

The receptor tyrosine kinase-like orphan receptor 1 (ROR1) sustains prosurvival signalling directly downstream of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinoma. Here we report an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. This kinase-independent function of ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane, thereby preventing the lysosomal degradation of CAV1. Caveolae structures and prosurvival signalling towards AKT through multiple RTKs are consequently sustained. These findings provide mechanistic insight into how ROR1 inhibition can overcome EGFR-tyrosine kinase inhibitor (TKI) resistance due to bypass signalling via diverse RTKs such as MET and IGF-IR, which is currently a major clinical obstacle. Considering its onco-embryonic expression, inhibition of the scaffold function of ROR1 in patients with lung adenocarcinoma is an attractive approach for improved treatment of this devastating cancer.

• Authors: Tomoya Yamaguchi, Can Lu, Lisa Ida, Kiyoshi Yanagisawa, Jiro Usukura, Jinglei Cheng, Naoe Hotta, Yukako Shimada, Hisanori Isomura, Motoshi Suzuki, Toyoshi Fujimoto, Takashi Takahashi
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 10060 (Jan 04 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 26725982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CAV1 protein, human
• CAVIN1 protein, human
• Caveolin 1
• RNA-Binding Proteins
• ErbB Receptors
• Protein-Tyrosine Kinases
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors

Topics

• Adenocarcinoma (therapy)
• Antineoplastic Agents (pharmacology)
• Caveolin 1 (genetics, metabolism)
• Cell Line, Tumor
• ErbB Receptors (genetics, metabolism)
• Humans
• Lung Neoplasms (therapy)
• Phosphorylation
• Protein Array Analysis
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• RNA-Binding Proteins (genetics, metabolism)
• Receptor Tyrosine Kinase-like Orphan Receptors (genetics, metabolism)
• Signal Transduction