Cancer Research 2014-07-15

Flotillin-1 regulates oncogenic signaling in neuroblastoma cells by regulating ALK membrane association.

Arata Tomiyama, Takamasa Uekita, Reiko Kamata, Kazuki Sasaki, Junko Takita, Miki Ohira, Akira Nakagawara, Chifumi Kitanaka, Kentaro Mori, Hideki Yamaguchi, Ryuichi Sakai

Index: Cancer Res. 74(14) , 3790-801, (2014)

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Abstract

Neuroblastomas harbor mutations in the nonreceptor anaplastic lymphoma kinase (ALK) in 8% to 9% of cases where they serve as oncogenic drivers. Strategies to reduce ALK activity offer clinical interest based on initial findings with ALK kinase inhibitors. In this study, we characterized phosphotyrosine-containing proteins associated with ALK to gain mechanistic insights in this setting. Flotillin-1 (FLOT1), a plasma membrane protein involved in endocytosis, was identified as a binding partner of ALK. RNAi-mediated attenuation of FLOT1 expression in neuroblastoma cells caused ALK dissociation from endosomes along with membrane accumulation of ALK, thereby triggering activation of ALK and downstream effector signals. These features enhanced the malignant properties of neuroblastoma cells in vitro and in vivo. Conversely, oncogenic ALK mutants showed less binding affinity to FLOT1 than wild-type ALK. Clinically, lower expression levels of FLOT1 were documented in highly malignant subgroups of human neuroblastoma specimens. Taken together, our findings suggest that attenuation of FLOT1-ALK binding drives malignant phenotypes of neuroblastoma by activating ALK signaling.©2014 American Association for Cancer Research.