title: 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.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Can
authors.initials: C
authors.lastname: Lu
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ida
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.affiliation: Division of Integrated Project, EcoTopia Science Institute, Nagoya University, Nagoya 464-8603, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Usukura
authors.affiliation: Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Jinglei
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Naoe
authors.initials: N
authors.lastname: Hotta
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Isomura
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Motoshi
authors.identifier: http://orcid.org/0000-0003-0682-5006
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Fujimoto
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000230:Adenocarcinoma / Q000628:therapy; D000970:Antineoplastic Agents / Q000494:pharmacology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy; D010766:Phosphorylation; D040081:Protein Array Analysis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; C495540:CAV1 protein, human; C497835:CAVIN1 protein, human; D051242:Caveolin 1; D016601:RNA-Binding Proteins; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors