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c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1

Oncogene volume 30, pages 2198–2206 (2011)Cite this article

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Abstract

Angiogenesis is regulated by highly coordinated function of various proteins with pro- and anti-angiogenic functions. Among the many cytoplasmic signaling proteins that are activated by VEGFR-2, activation of PLCγ1 is considered to have a pivotal role in angiogenic signaling. In previous study we have identified c-Cbl as a negative regulator of PLCγ1 in endothelial cells, the biochemical and biological significance of c-Cbl, however, in angiogenesis in vivo and molecular mechanisms involved were remained elusive. In this study, we report that genetic inactivation of c-Cbl in mice results in enhanced tumor angiogenesis and retinal neovascularization. Endothelial cells derived from c-Cbl null mice displayed elevated cell proliferation and tube formation in response to VEGF stimulation. Loss of c-Cbl also resulted in robust activation of PLCγ1 and increased intracellular calcium release. c-Cbl-dependent ubiquitination selectively inhibited tyrosine phosphorylation of PLCγ1 and mostly refrained from ubiquitin-mediated degradation. Hence, we propose c-Cbl as an angiogenic suppressor protein where upon activation it uniquely modulates PLCγ1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis.

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Acknowledgements

This study was supported by grants from the National Institutes of Health (NIH/NEI) to NR and Massachusetts Lions Foundation grant to Department of Ophthalmology, and also by BU CTSI grant (NR). The c-Cbl knockout mice were generously provided by Jeffrey Chiang (National Cancer Institute, Frederick, MD).Author contribution: Rosana D Meyer, Deeba Husain and Nader Rahimi all performed experiments. Nader Rahimi wrote the manuscript.

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Authors and Affiliations

  1. Department of Pathology, Boston University Medical Campus, Boston, MA, USA

    R D Meyer & N Rahimi

  2. Department of Ophthalmology, Boston University Medical Campus, Boston, MA, USA

    D Husain & N Rahimi

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  1. R D Meyer
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  2. D Husain
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  3. N Rahimi
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Correspondence to N Rahimi.

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Meyer, R., Husain, D. & Rahimi, N. c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1. Oncogene 30, 2198–2206 (2011). https://doi.org/10.1038/onc.2010.597

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