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Regulation of receptor for activated C kinase 1 protein by the von Hippel–Lindau tumor suppressor in IGF-I-induced renal carcinoma cell invasiveness

Oncogene volume 30, pages 535–547 (2011)Cite this article

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Abstract

von Hippel–Lindau (VHL) tumor suppressor loss is associated with renal cell carcinoma (RCC) pathogenesis. Meanwhile, aberrant activation of the insulin-like growth factor-I (IGF-I) signaling has been implicated in the development of highly invasive metastatic RCC. However, the link between VHL inactivation and RCC invasiveness is still unexplored. Here, we show that the receptor for activated C kinase 1 (RACK1) is a novel pVHL-interacting protein. pVHL competes with IGF-I receptor (IGF-IR) for binding to RACK1 thus potentially modulating the downstream IGF-I signal pathway. Upon IGF-I stimulation, pVHL-deficient RCC cells exhibit increased RACK1/IGF-IR binding and increased IGF-IR tyrosine kinase activity. pVHL-deficient RCC cells also demonstrate elevated PI3K/Akt signaling and matrix metalloproteinase-2 activity that culminates in enhanced cellular invasiveness, which can be partially suppressed by RACK1 small interfering RNA. Domain mapping analysis showed that the pVHL α-domain and the RACK1 WD 6–7 domains are critical for the interaction. Additionally, the RACK1 expression level is not regulated by pVHL expression status, suggesting that pVHL modifies RACK1 functions independent of the VHL/elongin E3 ubiquitin ligase complex. Our data indicate that RACK1 serves as a direct mediator between loss of pVHL function and enhanced IGF-IR signaling pathway in RCC.

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Acknowledgements

We thank Dr Patrick H Maxwell and Dr William G Kaelin Jr for their generous gifts of the RCC stable cell lines. We also thank Christopher R Silvers for his technical support. Funding: This work was supported in part by the James P Wilmot Cancer Center grant to X He.

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Authors and Affiliations

  1. Department of Urology, University of Rochester Medical Center, Rochester, NY, USA

    X He, E M Messing & G Wu

  2. Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA

    J Wang

  3. The James P Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA

    X He, E M Messing & G Wu

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Correspondence to G Wu.

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He, X., Wang, J., Messing, E. et al. Regulation of receptor for activated C kinase 1 protein by the von Hippel–Lindau tumor suppressor in IGF-I-induced renal carcinoma cell invasiveness. Oncogene 30, 535–547 (2011). https://doi.org/10.1038/onc.2010.427

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