This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pajusola, K. Articles by Alitalo, K. Search for Related Content PubMed PubMed Citation Articles by Pajusola, K. Articles by Alitalo, K.

FLT4 Receptor Tyrosine Kinase Contains Seven Immunoglobulin-like Loops and Is Expressed in Multiple Human Tissues and Cell Lines¹

Cancer Biology Laboratory, Departments of Virology [L. P.] and Pathology [K. P., O. A., J. K., A. K., K. A.], and Transplantation Laboratory [R. A.], University of Helsinki, Haartmaninkatu 3, 00290 Helsinki 29, Finland

The fms-like tyrosine kinase 4 (FLT4) complementary DNA was cloned from a human HEL erythroleukemia cell library by polymerase chain reaction-amplification. We previously reported a partial sequence of FLT4 and showed that the FLT4 gene maps to chromosomal region 5q33-qter (O. Aprelikova, K. Pajusola, J. Partanen, E. Armstrong, R. Alitalo, S. Bailey, J. McMahon, J. Wasmuth, K. Huebner, and K. Alitalo, Cancer Res., 52: 746–748, 1992). Here we present the full-length sequence of the predicted FLT4 protein. The extracellular domain of FLT4 consists of 7 immunoglobulin-like loops, including 12 potential glycosylation sites. On the basis of structural similarities FLT4 and the previously known FLT1 and kinase insert domain-containing receptor tyrosine kinase/fetal liver kinase 1 (KDR/FLK1) receptors constitute a subfamily of class III tyrosine kinases. FLT4 was expressed as 5.8- and 4.5-kilobase mRNAs which were found to differ in their 3' sequences and to be differentially expressed in the HEL and DAMI leukemia cells. Interestingly, a Wilms' tumor cell line, a retinoblastoma cell line, and a nondifferentiated teratocarcinoma cell line expressed FLT4, whereas differentiated teratocarcinoma cells were negative. Most fetal tissues also expressed the FLT4 mRNA, with spleen, brain intermediate zone, and lung showing the highest levels. In in situ hybridization the FLT4 autoradiographic grains decorated bronchial epithelial cells of fetal lung. No evidence was obtained for the expression of FLT4 in the endothelial cells of blood vessels.

¹ Supported by the Finnish Cancer Organizations, the Finnish Academy, and the Sigrid Juselius and Finnish Cultural Foundations.

² To whom requests for reprints should be addressed.

Received 5/ 4/92. Accepted 8/ 6/92.

This article has been cited by other articles:

				W. S. SHIN and S. G. ROCKSON Animal Models for the Molecular and Mechanistic Study of Lymphatic Biology and Disease Ann. N.Y. Acad. Sci., May 1, 2008; 1131(1): 50 - 74. [Abstract] [Full Text] [PDF]

				X. Qin, Y. Wan, M. Li, X. Xue, S. Wu, C. Zhang, Y. You, W. Wang, C. Jiang, Y. Liu, et al. Identification of a Novel Peptide Ligand of Human Vascular Endothelia Growth Factor Receptor 3 for Targeted Tumour Diagnosis and Therapy J. Biochem., July 1, 2007; 142(1): 79 - 85. [Abstract] [Full Text] [PDF]

				P. Laakkonen, M. Waltari, T. Holopainen, T. Takahashi, B. Pytowski, P. Steiner, D. Hicklin, K. Persaud, J. R. Tonra, L. Witte, et al. Vascular Endothelial Growth Factor Receptor 3 Is Involved in Tumor Angiogenesis and Growth Cancer Res., January 15, 2007; 67(2): 593 - 599. [Abstract] [Full Text] [PDF]

				C. Cursiefen, L. Chen, M. Saint-Geniez, P. Hamrah, Y. Jin, S. Rashid, B. Pytowski, K. Persaud, Y. Wu, J. W. Streilein, et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision PNAS, July 25, 2006; 103(30): 11405 - 11410. [Abstract] [Full Text] [PDF]

				M. Pieren, A. E. Prota, C. Ruch, D. Kostrewa, A. Wagner, K. Biedermann, F. K. Winkler, and K. Ballmer-Hofer Crystal Structure of the Orf Virus NZ2 Variant of Vascular Endothelial Growth Factor-E: IMPLICATIONS FOR RECEPTOR SPECIFICITY J. Biol. Chem., July 14, 2006; 281(28): 19578 - 19587. [Abstract] [Full Text] [PDF]

				R. R. Foster, S. C. Satchell, J. Seckley, M. S. Emmett, K. Joory, C. Y. Xing, M. A. Saleem, P. W. Mathieson, D. O. Bates, and S. J. Harper VEGF-C promotes survival in podocytes Am J Physiol Renal Physiol, July 1, 2006; 291(1): F196 - F207. [Abstract] [Full Text] [PDF]

				J. Kreuger, I. Nilsson, D. Kerjaschki, T. Petrova, K. Alitalo, and L. Claesson-Welsh Early Lymph Vessel Development From Embryonic Stem Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1073 - 1078. [Abstract] [Full Text] [PDF]

				G. Fuh, P. Wu, W.-C. Liang, M. Ultsch, C. V. Lee, B. Moffat, and C. Wiesmann Structure-Function Studies of Two Synthetic Anti-vascular Endothelial Growth Factor Fabs and Comparison with the AvastinTM Fab J. Biol. Chem., March 10, 2006; 281(10): 6625 - 6631. [Abstract] [Full Text] [PDF]

				R. Bhattacharya, S. SenBanerjee, Z. Lin, S. Mir, A. Hamik, P. Wang, P. Mukherjee, D. Mukhopadhyay, and M. K. Jain Inhibition of Vascular Permeability Factor/Vascular Endothelial Growth Factor-mediated Angiogenesis by the Kruppel-like Factor KLF2 J. Biol. Chem., August 12, 2005; 280(32): 28848 - 28851. [Abstract] [Full Text] [PDF]

				X. Zhang, J. F. Wang, B. Chandran, K. Persaud, B. Pytowski, J. Fingeroth, and J. E. Groopman Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection J. Biol. Chem., July 15, 2005; 280(28): 26216 - 26224. [Abstract] [Full Text] [PDF]

				M. Sugaya, T. Watanabe, A. Yang, M. F. Starost, H. Kobayashi, A. M. Atkins, D. L. Borris, E. A. Hanan, D. Schimel, M. A. Bryant, et al. Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter Blood, March 15, 2005; 105(6): 2356 - 2363. [Abstract] [Full Text] [PDF]

				N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF]

				Y. Zeng, K. Opeskin, M. E. Baldwin, L. G. Horvath, M. G. Achen, S. A. Stacker, R. L. Sutherland, and E. D. Williams Expression of Vascular Endothelial Growth Factor Receptor-3 by Lymphatic Endothelial Cells Is Associated with Lymph Node Metastasis in Prostate Cancer Clin. Cancer Res., August 1, 2004; 10(15): 5137 - 5144. [Abstract] [Full Text] [PDF]

				C. Feistritzer, N. C. Kaneider, D. H. Sturn, B. A. Mosheimer, C. M. Kahler, and C. J. Wiedermann Expression and Function of the Vascular Endothelial Growth Factor Receptor FLT-1 in Human Eosinophils Am. J. Respir. Cell Mol. Biol., May 1, 2004; 30(5): 729 - 735. [Abstract] [Full Text] [PDF]

				P. SAHARINEN and T. V. PETROVA Molecular Regulation of Lymphangiogenesis Ann. N.Y. Acad. Sci., April 1, 2004; 1014(1): 76 - 87. [Abstract] [Full Text] [PDF]

				F Belgore, A Blann, D Neil, A S Ahmed, and G Y H Lip Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries J. Clin. Pathol., March 1, 2004; 57(3): 266 - 272. [Abstract] [Full Text] [PDF]

				J. Dixelius, T. Makinen, M. Wirzenius, M. J. Karkkainen, C. Wernstedt, K. Alitalo, and L. Claesson-Welsh Ligand-induced Vascular Endothelial Growth Factor Receptor-3 (VEGFR-3) Heterodimerization with VEGFR-2 in Primary Lymphatic Endothelial Cells Regulates Tyrosine Phosphorylation Sites J. Biol. Chem., October 17, 2003; 278(42): 40973 - 40979. [Abstract] [Full Text] [PDF]

				D.C Felmeden, A.D Blann, and G.Y.H Lip Angiogenesis: basic pathophysiology and implications for disease Eur. Heart J., April 1, 2003; 24(7): 586 - 603. [Full Text] [PDF]

				A. SAARISTO, M. J. KARKKAINEN, and K. ALITALO Insights into the Molecular Pathogenesis and Targeted Treatment of Lymphedema Ann. N.Y. Acad. Sci., December 1, 2002; 979(1): 94 - 110. [Abstract] [Full Text] [PDF]

				S. A. STACKER, M. E. BALDWIN, and M. G. ACHEN The role of tumor lymphangiogenesis in metastatic spread FASEB J, July 1, 2002; 16(9): 922 - 934. [Abstract] [Full Text] [PDF]

				L. Jussila and K. Alitalo Vascular Growth Factors and Lymphangiogenesis Physiol Rev, July 1, 2002; 82(3): 673 - 700. [Abstract] [Full Text] [PDF]

				T. Matsumoto and L. Claesson-Welsh VEGF Receptor Signal Transduction Sci. Signal., December 11, 2001; 2001(112): re21 - re21. [Abstract] [Full Text] [PDF]

				K. ILJIN, M. J. KARKKAINEN, E. C. LAWRENCE, M. A. KIMAK, M. UUTELA, J. TAIPALE KATRI PAJUSOLA LEENA ALHONEN, M. HALMEKYTO, D. N. FINEGOLD, R. E. FERRELL, and K. ALITALO VEGFR3 gene structure, regulatory region, and sequence polymorphisms FASEB J, April 1, 2001; 15(6): 1028 - 1036. [Abstract] [Full Text] [PDF]

				C. Robinson and S. Stringer The splice variants of vascular endothelial growth factor (VEGF) and their receptors J. Cell Sci., January 3, 2001; 114(5): 853 - 865. [Abstract] [PDF]

				M. O. Hiltunen, M. Laitinen, M. P. Turunen, M. Jeltsch, J. Hartikainen, T. T. Rissanen, J. Laukkanen, M. Niemi, M. Kossila, T. P. Hakkinen, et al. Intravascular Adenovirus-Mediated VEGF-C Gene Transfer Reduces Neointima Formation in Balloon-Denuded Rabbit Aorta Circulation, October 31, 2000; 102(18): 2262 - 2268. [Abstract] [Full Text] [PDF]

				S. D. Nathanson, R. J. Zarbo, D. L. Wachna, C. A. Spence, T. A. Andrzejewski, and J. Abrams Microvessels That Predict Axillary Lymph Node Metastases in Patients With Breast Cancer Arch Surg, May 1, 2000; 135(5): 586 - 594. [Abstract] [Full Text] [PDF]

				H. Oh, H. Takagi, K. Suzuma, A. Otani, M. Matsumura, and Y. Honda Hypoxia and Vascular Endothelial Growth Factor Selectively Up-regulate Angiopoietin-2 in Bovine Microvascular Endothelial Cells J. Biol. Chem., May 28, 1999; 274(22): 15732 - 15739. [Abstract] [Full Text] [PDF]

				A. Lymboussaki, T. A. Partanen, B. Olofsson, J. Thomas-Crusells, C. D. M. Fletcher, R. M. W. de Waal, A. Kaipainen, and K. Alitalo Expression of the Vascular Endothelial Growth Factor C Receptor VEGFR-3 in Lymphatic Endothelium of the Skin and in Vascular Tumors Am. J. Pathol., August 1, 1998; 153(2): 395 - 403. [Abstract] [Full Text] [PDF]

				J.-F. Wang, R. K. Ganju, Z.-Y. Liu, H. Avraham, S. Avraham, and J. E. Groopman Signal Transduction in Human Hematopoietic Cells by Vascular Endothelial Growth Factor Related Protein, a Novel Ligand for the FLT4 Receptor Blood, November 1, 1997; 90(9): 3507 - 3515. [Abstract] [Full Text] [PDF]

				N. Ferrara and T. Davis-Smyth The Biology of Vascular Endothelial Growth Factor Endocr. Rev., February 1, 1997; 18(1): 4 - 25. [Abstract] [Full Text]

				K. Paavonen, N. Horelli-Kuitunen, D. Chilov, E. Kukk, S. Pennanen, O.-P. Kallioniemi, K. Pajusola, B. Olofsson, U. Eriksson, V. Joukov, et al. Novel Human Vascular Endothelial Growth Factor Genes VEGF-B and VEGF-C Localize to Chromosomes 11q13 and 4q34, Respectively Circulation, March 15, 1996; 93(6): 1079 - 1082. [Abstract] [Full Text]

				M. Nomura, S.-i. Yamagishi, S.-i. Harada, Y. Hayashi, T. Yamashima, J. Yamashita, and H. Yamamoto Possible Participation of Autocrine and Paracrine Vascular Endothelial Growth Factors in Hypoxia-induced Proliferation of Endothelial Cells and Pericytes J. Biol. Chem., November 24, 1995; 270(47): 28316 - 28324. [Abstract] [Full Text] [PDF]

				D J Dumont, G Gradwohl, G H Fong, M C Puri, M Gertsenstein, A Auerbach, and M L Breitman Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes & Dev., August 15, 1994; 8(16): 1897 - 1909. [Abstract] [PDF]

				M. Papetti and I. M. Herman Mechanisms of normal and tumor-derived angiogenesis Am J Physiol Cell Physiol, May 1, 2002; 282(5): C947 - C970. [Abstract] [Full Text] [PDF]