Processing of VEGF-C and -Dby the Proprotein Convertases

Processing of VEGF-C and -Dby the Proprotein Convertases
Importance in Angiogenesis, Lymphangiogenesis, and Tumorigenesis

Geraldine Siegfried, Abdel-Majid Khatib
ISBN: 9781615046102 | PDF ISBN: 9781615046119
Copyright © 2013 | 66 Pages | Publication Date: 11/01/2013

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The vascular endothelial growth factor (VEGF) family members that include VEGF-A, -B, -C, -D, and placental growth factor (PlGF), display distinct binding affinities for their receptors VEGFR-1, -2, and/or -3. In addition to their requirements in the initiation, development, and maintenance of blood and lymphatic vasculature, VEGFs and VEGFRs are upregulated during neoplasia and are involved in the remodeling of tumoral blood and lymphatic vasculature. By activating VEGFR-1 and VEGFR-2, both expressed on blood endothelial cells, VEGF-A promotes the formation of new tumoral blood vessels and thereby accelerates tumor growth. In contrast, upregulation of VEGF-C, a ligand for lymphatic endothelial VEGFR-3 as well as for VEGFR-2, induces the formation of tumor-associated lymphatic vessels and thus promotes the passive metastatic dissemination of tumor cells to regional lymph nodes. Of the VEGF family members, only VEGF-C and -D were found to be proteolytically processed by Furin-like enzymes. This processing controls the selective activation of VEGFR-2 and -3 signaling during tumor angiogenesis and lymphangiogenesis. Here, we provide an overview of angiogenesis processes and discuss the importance of VEGF-C and VEGF-D precursors processing by the proprotein convertases during the activation of VEGFR-2 and VEGFR-3 receptors and the mediation of their functions during angiogenesis, lymphangiogenesis, and tumorigenesis.

Table of Contents

Abbreviations
Acknowledgments
Angiogenesis: A Global Overview
VEGF Family Members, Their Receptors, and Signaling
Activation, Signaling, and Function of VEGFRs
The Role of VEGF Family Members in Tumor Angiogenesis and Lymphangiogenesis
Maturation of VEGF-C and VEGF-D by the Proprotein Convertases
References
Author Biographies

About the Author(s)

Geraldine Siegfried, University of Bordeaux, LAMC, UMR 1029, F-3400 and INSERM U1029, France
Dr. Geraldine Siegfried received her PhD in Physiology from Paris 7 University in 1996. Geraldine was a postdoctoral fellow from 1996 to 1999 at McGill University (Canada) and from 1999 to 2001 at the University of Montreal (Canada). She joined the INSERM and University of Paris 11 in 2005 as a Scientist. Geraldine’s research program focuses on the importance of the proprotein convertases in the processes of angiogenesis. She revealed that several important angiogenic factors are substrates of the proprotein convertases including PDGF-A and -B and VEGF-C and demonstrated the importance of their cleavage in the mediation of their functions during physiological circumstances and pathological situations.

Abdel-Majid Khatib, University of Bordeaux, LAMC, UMR 1029, F-3400 and INSERM U1029, France
Dr. Majid Khatib obtained his PhD from the University of Paris in 1997 and then completed his postdoctoral training at McGill University (Montreal, Canada). Starting in 2002, he directed his own laboratory as Scientist at the Ottawa Hospital Research Institute (OHRI), University of Ottawa (Ontario, Canada). Since 2008, he has been a research director at INSERM, first at the Hospital St-Louis in Paris and now at the University of Bordeaux. While a postdoctoral fellow, he demonstrated experimentally the implications of the proprotein convertases in the malignant phenotype of tumor cells. His work revealed at that time that the inhibition of the proprotein convertases may constitute a new potential opportunity in anticancer therapy. His research team has since discovered and characterized various substrates of these proteases and demonstrated the importance of their processing in the mediation of neoplasia. The laboratory of Dr. Khatib is also interested in the identification of small molecules inhibitors able to block the maturation of the PC substrates and reduce the malignant phenotype of tumor cells. Dr. Khatib has published many articles and reviews dealing with the importance of the proprotein convertases and their inhibitors in cancer.

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