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      Cullin-3 and its adaptor protein ANKFY1 determine the surface level of integrin β1 in endothelial cells

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          Angiogenesis, the formation of new blood vessels from the pre-existing vasculature, is related to numerous pathophysiological events. We previously reported that a RING ubiquitin ligase complex scaffold protein, cullin-3 (CUL3), and one of its adaptor proteins, BAZF, regulated angiogenesis in the mouse retina by suppressing Notch signaling. However, the degree of inhibition of angiogenesis was made greater by CUL3 depletion than by BAZF depletion, suggesting other roles of CUL3 in angiogenesis besides the regulation of Notch signaling. In the present study, we found that CUL3 was critical for the cell surface level of integrin β1, an essential cell adhesion molecule for angiogenesis in HUVECs. By siRNA screening of 175 BTBPs, a family of adaptor proteins for CUL3, we found that ANKFY1/Rabankyrin-5, an early endosomal BTBP, was also critical for localization of surface integrin β1 and angiogenesis. CUL3 interacted with ANKFY1 and was required for the early endosomal localization of ANKFY1. These data suggest that CUL3/ANKFY1 regulates endosomal membrane traffic of integrin β1. Our results highlight the multiple roles of CUL3 in angiogenesis, which are mediated through distinct CUL3-adaptor proteins.


          Summary: CUL3 and a CUL3-binding protein ANKFY1 determined the surface expression of integrin β1, an essential adhesion molecule for angiogenesis, by regulating the endosomal recycling traffic of integrin β1.

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          Most cited references 48

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          Integrins: bidirectional, allosteric signaling machines.

          In their roles as major adhesion receptors, integrins signal across the plasma membrane in both directions. Recent structural and cell biological data suggest models for how integrins transmit signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways. Long-range conformational changes couple these functions via allosteric equilibria.
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            Molecular mechanisms and clinical applications of angiogenesis.

            Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
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              Modes of resistance to anti-angiogenic therapy.

              Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.

                Author and article information

                [1 ]Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University , Matsuyama 791-0295, Japan
                [2 ]Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine , Matsuyama 791-0295, Japan
                [3 ]Department of Gastrointestinal Surgery and Surgical Oncology, Ehime University Graduate School of Medicine , Matsuyama 791-0295, Japan
                [4 ]Department of Cardiovascular and Thoracic Surgery, Ehime University Graduate School of Medicine , Matsuyama 791-0295, Japan
                [5 ]Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences , Nagoya City 467-8601, Japan
                [6 ]Department of Health Chemistry, Graduate School of Pharmaceutical Science, University of Tokyo , Tokyo 113-0033, Japan
                [7 ]Pathological Cell Biology Laboratory, Graduate School of Pharmaceutical Science, University of Tokyo , Tokyo 113-0033, Japan
                Author notes

                These authors contributed equally to this work

                Biol Open
                Biol Open
                Biology Open
                The Company of Biologists Ltd
                15 November 2017
                16 October 2017
                16 October 2017
                : 6
                : 11
                : 1707-1719
                © 2017. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                Funded by: Japan Society for the Promotion of Science,;
                Award ID: JP16K19038
                Award ID: JP16H046980
                Funded by: Ehime Industrial Promotion Foundation;
                Funded by: Kanae Foundation for the Promotion of Medical Science,;
                Funded by: Novartis Pharmaceuticals Research;
                Funded by: Japan Agency for Medical Research and Development,;
                Award ID: AMED 16cm0106219h0001
                Research Article

                Life sciences

                angiogenesis, endothelial cells, membrane trafficking, integrin, cullin-3 (cul3)


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