Vascular Endothelial Growth Factor D (VEGF-D) is a Ligand for the Tyrosine Kinases VEGF Receptor 2 (Flk1) and VEGF Receptor 3 (Flt4)

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1998 Jan 22

PMID 9435229

Citations 319

Authors

M G Achen

M Jeltsch

E Kukk

T Makinen

A Vitali

A F Wilks

K Alitalo

S A Stacker

Affiliations

Soon will be listed here.

Abstract

We have identified a member of the VEGF family by computer-based homology searching and have designated it VEGF-D. VEGF-D is most closely related to VEGF-C by virtue of the presence of N- and C-terminal extensions that are not found in other VEGF family members. In adult human tissues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, colon, and small intestine. Analyses of VEGF-D receptor specificity revealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors. However. VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary structure to other VEGF family members and that corresponds to the mature form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cells. The structural and functional similarities between VEGF-D and VEGF-C define a subfamily of the VEGFs.

Citing Articles

Beyond vessels: unraveling the impact of VEGFs on neuronal functions and structure.

Aksan B, Mauceri D J Biomed Sci. 2025; 32(1):33.

PMID: 40050849 PMC: 11884128. DOI: 10.1186/s12929-025-01128-8.

Contagious ecthyma in small ruminants: from etiology to vaccine challenges - a review.

Reichen C, Beirao B, Monteiro A Vet Res Commun. 2025; 49(2):115.

PMID: 39992468 DOI: 10.1007/s11259-025-10677-0.

Lymphatic complication in open venous harvesting versus endoscopic venous harvesting: a systematic review and meta-analysis.

Razavi A, Mahalleh M, Vanaki A, Fallah A, Bahanesteh A, Ahmadi A Gen Thorac Cardiovasc Surg. 2025; .

PMID: 39962020 DOI: 10.1007/s11748-025-02126-1.

sVEGFR3 alleviates myocardial ischemia/reperfusion injury through regulating mitochondrial homeostasis and immune cell infiltration.

Shang L, Ao Y, Huang X, Wu H, Feng K, Wang J Apoptosis. 2025; .

PMID: 39863719 DOI: 10.1007/s10495-024-02068-8.

Advances in molecular imaging and targeted therapeutics for lymph node metastasis in cancer: a comprehensive review.

Wu Y, Shang J, Zhang X, Li N J Nanobiotechnology. 2024; 22(1):783.

PMID: 39702277 PMC: 11657939. DOI: 10.1186/s12951-024-02940-4.

References

Lennon G, Auffray C, Polymeropoulos M, Soares M . The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics. 1996; 33(1):151-2. DOI: 10.1006/geno.1996.0177. View

Weindel K, Marme D, Weich H . AIDS-associated Kaposi's sarcoma cells in culture express vascular endothelial growth factor. Biochem Biophys Res Commun. 1992; 183(3):1167-74. DOI: 10.1016/s0006-291x(05)80313-4. View

Orlandini M, Marconcini L, Ferruzzi R, Oliviero S . Identification of a c-fos-induced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family. Proc Natl Acad Sci U S A. 1996; 93(21):11675-80. PMC: 38117. DOI: 10.1073/pnas.93.21.11675. View

Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V . VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development. 1996; 122(12):3829-37. DOI: 10.1242/dev.122.12.3829. View

Risau W . Mechanisms of angiogenesis. Nature. 1997; 386(6626):671-4. DOI: 10.1038/386671a0. View

Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H . Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 1997; 276(5317):1423-5. DOI: 10.1126/science.276.5317.1423. View

Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y . Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997; 16(13):3898-911. PMC: 1170014. DOI: 10.1093/emboj/16.13.3898. View

Senger D, Galli S, Dvorak A, Perruzzi C, Harvey V, Dvorak H . Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983; 219(4587):983-5. DOI: 10.1126/science.6823562. View

Fung M, Hapel A, Ymer S, Cohen D, Johnson R, Campbell H . Molecular cloning of cDNA for murine interleukin-3. Nature. 1984; 307(5948):233-7. DOI: 10.1038/307233a0. View

10.

von Heijne G . A new method for predicting signal sequence cleavage sites. Nucleic Acids Res. 1986; 14(11):4683-90. PMC: 311474. DOI: 10.1093/nar/14.11.4683. View

11.

Aruffo A, Seed B . Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc Natl Acad Sci U S A. 1987; 84(23):8573-7. PMC: 299587. DOI: 10.1073/pnas.84.23.8573. View

12.

DAndrea A, Lodish H, Wong G . Expression cloning of the murine erythropoietin receptor. Cell. 1989; 57(2):277-85. DOI: 10.1016/0092-8674(89)90965-3. View

13.

Pearson W . Rapid and sensitive sequence comparison with FASTP and FASTA. Methods Enzymol. 1990; 183:63-98. DOI: 10.1016/0076-6879(90)83007-v. View

14.

Breier G, Albrecht U, Sterrer S, Risau W . Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development. 1992; 114(2):521-32. DOI: 10.1242/dev.114.2.521. View

15.

Folkman J, Shing Y . Angiogenesis. J Biol Chem. 1992; 267(16):10931-4. View

16.

Ostman A, Thyberg J, Westermark B, Heldin C . PDGF-AA and PDGF-BB biosynthesis: proprotein processing in the Golgi complex and lysosomal degradation of PDGF-BB retained intracellularly. J Cell Biol. 1992; 118(3):509-19. PMC: 2289541. DOI: 10.1083/jcb.118.3.509. View

17.

Maglione D, Guerriero V, Viglietto G, Ferraro M, Aprelikova O, Alitalo K . Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14. Oncogene. 1993; 8(4):925-31. View

18.

Millauer B, Schnurch H, Martinez R, Moller N, Risau W, Ullrich A . High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993; 72(6):835-46. DOI: 10.1016/0092-8674(93)90573-9. View

19.

McDonald N, Hendrickson W . A structural superfamily of growth factors containing a cystine knot motif. Cell. 1993; 73(3):421-4. DOI: 10.1016/0092-8674(93)90127-c. View

20.

Pajusola K, Aprelikova O, Armstrong E, Morris S, Alitalo K . Two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy terminal tails are produced by alternative processing of primary transcripts. Oncogene. 1993; 8(11):2931-7. View