RRC ID 51581
著者 Yamaguchi T, Lu C, Ida L, Yanagisawa K, Usukura J, Cheng J, Hotta N, Shimada Y, Isomura H, Suzuki M, Fujimoto T, Takahashi T.
タイトル ROR1 sustains caveolae and survival signalling as a scaffold of cavin-1 and caveolin-1.
ジャーナル Nat Commun
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.
巻・号 7
ページ 10060
公開日 2016-1-4
DOI 10.1038/ncomms10060
PII ncomms10060
PMID 26725982
PMC PMC4777216
MeSH Adenocarcinoma / therapy Antineoplastic Agents / pharmacology Caveolin 1 / genetics Caveolin 1 / metabolism* Cell Line, Tumor ErbB Receptors / genetics ErbB Receptors / metabolism Humans Lung Neoplasms / therapy Phosphorylation Protein Array Analysis Protein-Tyrosine Kinases / antagonists & inhibitors RNA-Binding Proteins / genetics RNA-Binding Proteins / metabolism* Receptor Tyrosine Kinase-like Orphan Receptors / genetics Receptor Tyrosine Kinase-like Orphan Receptors / metabolism* Signal Transduction
IF 12.121
引用数 39
リソース情報
ヒト・動物細胞 PC-9(RCB4455)