Biosynthesis of Vascular Endothelial Growth Factor-D Involves Proteolytic Processing Which Generates Non-covalent Homodimers

Stacker, Steven A.; Stenvers, Kaye L.; Caesar, Carol; Vitali, Angela; Domagała, Teresa; Nice, Edouard C.; Roufail, Sally; Simpson, Richard J.; Moritz, Robert L.; Kärpänen, Terhi; Alitalo, Kari; Achen, Marc G.

doi:10.1074/jbc.274.45.32127

Cited by 299 publications

(408 citation statements)

References 40 publications

(22 reference statements)

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“…Subsequently, the propeptides can be proteolytically removed to generate mature forms consisting of VHD dimers. The full-length forms of both growth factors bind the lymphangiogenic receptor VEGFR-3 but the mature forms do so with greater affinity (Joukov et al, 1997;Stacker et al, 1999), suggesting that the degree of proteolytic processing of VEGF-C and VEGF-D may in part determine the extent of lymphangiogenesis induced by these proteins in a tumour. Once VEGF-C is processed to the mature form it acquires the capacity to bind VEGFR-2 (Joukov et al, 1997), a cell surface receptor tyrosine kinase thought to signal for angiogenesis.…”

Section: Mechanisms Of Lymphangiogenic Signallingmentioning

confidence: 99%

“…Once VEGF-C is processed to the mature form it acquires the capacity to bind VEGFR-2 (Joukov et al, 1997), a cell surface receptor tyrosine kinase thought to signal for angiogenesis. In the case of VEGF-D, the affinity for VEGFR-2 is increased approximately 290-fold by proteolytic conversion of the full-length to the mature form (Stacker et al, 1999). Hence the mature forms of VEGF-C and VEGF-D can induce angiogenesis (Cao et al, 1998;Rissanen et al, 2003).…”

Section: Mechanisms Of Lymphangiogenic Signallingmentioning

confidence: 99%

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Targeting lymphangiogenesis to prevent tumour metastasis

2006

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Recent studies involving animal models of cancer and clinicopathological analyses of human tumours suggest that the growth of lymphatic vessels (lymphangiogenesis) in or nearby tumours is associated with the metastatic spread of cancer. The best validated molecular signalling system for tumour lymphangiogenesis involves the secreted proteins vascular endothelial growth factor-C (VEGF-C) and VEGF-D that induce growth of lymphatic vessels via activation of VEGF receptor-3 (VEGFR-3) localised on the surface of lymphatic endothelial cells. In this review, we discuss the evidence supporting a role for this signalling system in the spread of cancer and potential approaches for blocking this system to prevent tumour metastasis.

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Section: Mechanisms Of Lymphangiogenic Signallingmentioning

confidence: 99%

Section: Mechanisms Of Lymphangiogenic Signallingmentioning

confidence: 99%

Targeting lymphangiogenesis to prevent tumour metastasis

2006

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“…They are specific ligands for the tyrosine kinase receptor, vascular endothelial growth factor receptor (VEGFR)-3 (flt-4) (Joukov et al, 1996;Achen et al, 1998). Both cytokines are subject to proteolytic processing, which also enables them to act as ligands for VEGFR2 (KDR/flk-1) Stacker et al, 1999). Vascular endothelial growth factor receptor 2 is expressed on vascular endothelial cells and is essential for the embryonic differentiation of endothelial and haematopoietic cells and formation of blood vessels (reviewed in Veikkola et al, 2000).…”

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confidence: 99%

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

Duff

Jeziorska

et al. 2003

Br J Cancer

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“…Of interest, blood vascular endothelial cells also express VEGF-C , suggesting possible paracrine mechanisms by which the blood vascular system may control lymphatic vessel growth and/or maintenance. Both VEGF-C and VEGF-D are produced as precursor proteins with N-and C-terminal propeptides flanking the VEGF homology domain Stacker et al, 1999). The secreted factors undergo proteolytic processing that results in increased affinity for VEGFR-2 and, consequently, in their ability to induce angiogenesis in vivo (Cao et al, 1998).…”

Section: Vegf-c and Vegf-dmentioning

confidence: 99%

Development of the lymphatic vascular system: A mystery unravels

Hong

Shin

Detmar

2004

Developmental Dynamics

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The blood vascular and the lymphatic system play complementary roles in tissue perfusion and fluid reabsorption. Despite its critical role in mediating tissue fluid homeostasis, intestinal lipid absorption, and the immune response, the lymphatic system has not received as much attention as the blood vascular system, largely due to a lack of lymphatic-specific markers and to the dearth of knowledge about the molecular regulation of lymphatic development and function. A series of recent landmark studies now significantly has advanced our understanding of the lymphatic system. Based upon the discovery and characterization of lymphatic-specific growth factors, receptors, and transcriptional regulators, the mystery of lymphatic vascular system development begins to be unraveled. The successful isolation and cultivation of blood vascular and lymphatic endothelial cells has enabled comparative molecular and cellular analyses of these two genetically and developmentally closely related cell lineages. Moreover, studies of several genetic mouse models have set the framework for a new molecular model of embryonic lymphatic vascular development and have identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Although these rapid advances already have led to development of the first lymphatic-targeted molecular therapies, there still remain many unanswered questions regarding almost every aspect of lymphatic vascular biology, making the lymphatic system a highly exciting and rewarding field of study.

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Biosynthesis of Vascular Endothelial Growth Factor-D Involves Proteolytic Processing Which Generates Non-covalent Homodimers

Cited by 299 publications

References 40 publications

Targeting lymphangiogenesis to prevent tumour metastasis

Targeting lymphangiogenesis to prevent tumour metastasis

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

Development of the lymphatic vascular system: A mystery unravels

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