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Kari Alitalo - One of the best experts on this subject based on the ideXlab platform.
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vegfc FLT4 signalling is suppressed by dll4 in developing zebrafish intersegmental arteries
Development, 2009Co-Authors: Benjamin M Hogan, Kari Alitalo, Robert Herpers, Merlijn Witte, Hanna Helotera, Hendricus J Duckers, Stefan SchultemerkerAbstract:The development of arteries, veins and lymphatics from pre-existing vessels are intimately linked processes controlled by a number of well-studied reiteratively acting signalling pathways. To delineate the mechanisms governing vessel formation in vivo, we performed a forward genetic screen in zebrafish and isolated the mutant expando. Molecular characterisation revealed a loss-of-function mutation in the highly conserved kinase insert region of FLT4. Consistent with previous reports, FLT4 mutants were deficient in lymphatic vascular development. Recent studies have demonstrated a role for FLT4 in blood vessels and showed that Dll4 limits angiogenic potential by limiting FLT4 function in developing blood vessels. We found that arterial angiogenesis proceeded normally, yet the dll4 loss-of-function arterial hyperbranching phenotype was rescued, in FLT4 signalling mutants. Furthermore, we found that the FLT4 ligand Vegfc drives arterial hyperbranching in the absence of dll4. Upon knockdown of dll4, intersegmental arteries were sensitised to increased vegfc levels and the overexpression of dll4 inhibited Vegfc/FLT4-dependent angiogenesis events. Taken together, these data demonstrate that dll4 functions to suppress the ability of developing intersegmental arteries to respond to Vegfc-driven FLT4 signalling in zebrafish. We propose that this mechanism contributes to the differential response of developing arteries and veins to a constant source of Vegfc present in the embryo during angiogenesis.
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Vegfc/FLT4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries
Development, 2009Co-Authors: Benjamin M Hogan, Kari Alitalo, Robert Herpers, Merlijn Witte, Hanna Helotera, Hendricus J Duckers, Stefan Schulte-merkerAbstract:The development of arteries, veins and lymphatics from pre-existing vessels are intimately linked processes controlled by a number of well-studied reiteratively acting signalling pathways. To delineate the mechanisms governing vessel formation in vivo, we performed a forward genetic screen in zebrafish and isolated the mutant expando. Molecular characterisation revealed a loss-of-function mutation in the highly conserved kinase insert region of FLT4. Consistent with previous reports, FLT4 mutants were deficient in lymphatic vascular development. Recent studies have demonstrated a role for FLT4 in blood vessels and showed that Dll4 limits angiogenic potential by limiting FLT4 function in developing blood vessels. We found that arterial angiogenesis proceeded normally, yet the dll4 loss-of-function arterial hyperbranching phenotype was rescued, in FLT4 signalling mutants. Furthermore, we found that the FLT4 ligand Vegfc drives arterial hyperbranching in the absence of dll4. Upon knockdown of dll4, intersegmental arteries were sensitised to increased vegfc levels and the overexpression of dll4 inhibited Vegfc/FLT4-dependent angiogenesis events. Taken together, these data demonstrate that dll4 functions to suppress the ability of developing intersegmental arteries to respond to Vegfc-driven FLT4 signalling in zebrafish. We propose that this mechanism contributes to the differential response of developing arteries and veins to a constant source of Vegfc present in the embryo during angiogenesis.
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vascular endothelial growth factor vegf like protein from orf virus nz2 binds to vegfr2 and neuropilin 1
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Lyn M Wise, Stephen B. Fleming, Andrew A. Mercer, Kari Alitalo, Loreen J Savory, Tanja Veikkola, Carol Caesar, Angela A Vitali, Taija Makinen, Steven A StackerAbstract:Orf virus, a member of the poxvirus family, produces a pustular dermatitis in sheep, goats, and humans. The lesions induced after infection with orf virus show extensive proliferation of vascular endothelial cells, dilation of blood vessels and dermal swelling. An explanation for the nature of these lesions may lie in the discovery that orf virus encodes an apparent homolog of the mammalian vascular endothelial growth factor (VEGF) family of molecules. These molecules mediate endothelial cell proliferation, vascular permeability, angiogenesis, and lymphangiogenesis via the endothelial cell receptors VEGFR-1 (Flt1), VEGFR-2 (KDR/Flk1), and VEGFR-3 (FLT4). The VEGF-like protein of orf virus strain NZ2 (ORFV2-VEGF) is most closely related in primary structure to VEGF. In this study we examined the biological activities and receptor specificity of the ORFV2-VEGF protein. ORFV2-VEGF was found to be a disulfide-linked homodimer with a subunit of ≈25 kDa. ORFV2-VEGF showed mitogenic activity on bovine aortic and human microvascular endothelial cells and induced vascular permeability. ORFV2-VEGF was found to bind and induce autophosphorylation of VEGFR-2 and was unable to bind or activate VEGFR-1 and VEGFR-3, but bound the newly identified VEGF165 receptor neuropilin-1. These results indicate that, from a functional viewpoint, ORFV2-VEGF is indeed a member of the VEGF family of molecules, but is unique, however, in that it utilizes only VEGFR-2 and neuropilin-1.
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lymphatic endothelial tumors induced by intraperitoneal injection of incomplete freund s adjuvant
Experimental Cell Research, 1999Co-Authors: Sabrina Mancardi, Giorgio Stanta, Nelson Dusetti, Marco Bestagno, Lotta Jussila, Marina Zweyer, Giancarlo Lunazzi, Daniel J Dumont, Kari Alitalo, Oscar R BurroneAbstract:Abstract Endothelial cells form the inner lining of blood and lymphatic vessels. In mice, only tumors of the blood vessel endothelium (haemangiomas) have been thus far reported. Here we describe a highly reproducible method for the induction of benign tumors of the lymphatic endothelial cells (lymphangiomas) in mice by intraperitoneal injection of incomplete Freund's adjuvant. Morphological and histopathological studies of the lesions revealed the presence of cells at various levels of vascular development. The lymphangiomas developed in the peritoneal cavity and expressed the endothelial markers CD31/PECAM (platelet endothelial cell adhesion molecule), CD54/ICAM-1 (InterCellular Adhesion Molecule-1), and CD102/ICAM-2, as well as the vascular endothelial growth factor (VEGF) receptor Flk-1, the endothelial cell specific receptors Tie-1 and Tie-2 and the lymphatic endothelial cell specific FLT4 receptor as shown by in situ hybridization. The Flk-1 and FLT4 receptors were also identified in immunoblots of the tumors and in cells cultured from them. When induced in β-galactosidase knock-in FLT4 +/− mice, the tumor endothelia could be stained blue in a number of tumor cells although the staining was of lower intensity than in normal lymphatic vessels. The tumor-derived cells could be propagated in vitro and they spontaneously differentiated, forming vessel-like structures. Murine lymphangiomas thus represent a highly reproducible and convenient source of lymphatic endothelial cells.
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a novel vascular endothelial growth factor vegf c is a ligand for the FLT4 vegfr 3 and kdr vegfr 2 receptor tyrosine kinases
The EMBO Journal, 1996Co-Authors: Vladimir Joukov, Katri Pajusola, Arja Kaipainen, Dmitri Chilov, Isto Lahtinen, Eola Kukk, Olli Saksela, Nisse Kalkkinen, Kari AlitaloAbstract:Angiogenesis, the sprouting of new blood vessels from pre-existing ones, and the permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). The FLT4 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. In this study, we have purified the FLT4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells. While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) family, its C-terminal half contains extra cysteine-rich motifs characteristic of a protein component of silk produced by the larval salivary glands of the midge, Chironomus tentans. VEGF-C is proteolytically processed, binds FLT4, which we rename as VEGFR-3 and induces tyrosine autophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulated the migration of bovine capillary endothelial cells in collagen gel. VEGF-C is thus a novel regulator of endothelia, and its effects may extend beyond the lymphatic system, where FLT4 is expressed.
Katri Pajusola - One of the best experts on this subject based on the ideXlab platform.
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a novel vascular endothelial growth factor vegf c is a ligand for the FLT4 vegfr 3 and kdr vegfr 2 receptor tyrosine kinases
The EMBO Journal, 1996Co-Authors: Vladimir Joukov, Katri Pajusola, Arja Kaipainen, Dmitri Chilov, Isto Lahtinen, Eola Kukk, Olli Saksela, Nisse Kalkkinen, Kari AlitaloAbstract:Angiogenesis, the sprouting of new blood vessels from pre-existing ones, and the permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). The FLT4 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. In this study, we have purified the FLT4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells. While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) family, its C-terminal half contains extra cysteine-rich motifs characteristic of a protein component of silk produced by the larval salivary glands of the midge, Chironomus tentans. VEGF-C is proteolytically processed, binds FLT4, which we rename as VEGFR-3 and induces tyrosine autophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulated the migration of bovine capillary endothelial cells in collagen gel. VEGF-C is thus a novel regulator of endothelia, and its effects may extend beyond the lymphatic system, where FLT4 is expressed.
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FLT4 FLT4 receptor ptk vertebrates
The Protein Kinase FactsBook#R##N#Protein-Serine Kinases, 1995Co-Authors: Katri Pajusola, Arja Kaipainen, Kari AlitaloAbstract:FLT4 is a PTK of the vascular endothelial growth factor (VEGF) (Flt1) receptor class. FLT4 does not bind VEGF, but a novel ligand instead. FLT4 is translated as a precursor form, which is proteolytically processed into an N-terminal subunit containing a major part of the extracellular domain, and a C-terminal subunit containing the transmembrane and intracellular regions. The subunits are held together by disulphide bonds. The FLT4 gene is expressed as two mRNAs (FLT4s and FLT4l) differing in their 3′ 2 coding sequences because of alternative polyadenylation and splicing. FLT4 shows the typical structure of receptor-type PTK, with a ligand-binding extracellular domain, a transmembrane domain, and an intracellular kinase domain with an insert region. The extracellular part comprises seven immunoglobulin homology domains with disulphide bonds.
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signalling properties of FLT4 a proteolytically processed receptor tyrosine kinase related to two vegf receptors
Oncogene, 1994Co-Authors: Katri Pajusola, Olga Aprelikova, Giuliana Pelicci, Herbert A Weich, Lena Claessonwelsh, Kari AlitaloAbstract:The FLT4, FLT1 and KDR/FLK1 genes encode structurally similar endothelial cell receptor tyrosine kinases. Recently it has been shown that the FLT1 and KDR/FLK-1 proteins function as high-affinity receptors for vascular endothelial growth factor (VEGF). Here we show that FLT4 does not act as a receptor for VEGF, as VEGF did not show specific binding to the FLT4 tyrosine kinase or induce its autophosphorylation. Also, FLT4 did not interact with KDR in response to VEGF. However, when fused with the ligand binding domain of the colony stimulating factor-1 receptor (CSF-1R), the FLT4 tyrosine kinase was specifically activated by CSF-1. The activated FLT4 tyrosine kinase domain was found to interact with the Src homology 2 domains of the SHC and GRB2 adaptor proteins in vitro and with SHC in cells. CSF-1 stimulation of the CSF-1R/FLT4 receptor chimera induced thymidine incorporation in serum-starved NIH3T3 fibroblasts, but not in porcine aortic or murine lung capillary endothelial cells, although tyrosyl phosphorylation of the receptor and SHC occurred in these cells as well. These results suggest that the endothelial cell FLT4 receptor tyrosine kinase transmits signals for an as yet unidentified growth factor.
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The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells.
The Journal of experimental medicine, 1993Co-Authors: Arja Kaipainen, Katri Pajusola, Olga Aprelikova, Jaana Korhonen, M G Persico, B I Terman, Kari AlitaloAbstract:The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.
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two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy terminal tails are produced by alternative processing of primary transcripts
Oncogene, 1993Co-Authors: Katri Pajusola, Olga Aprelikova, Elina Armstrong, S Morris, Kari AlitaloAbstract:Abstract FLT4 is a recently cloned gene encoding a transmembrane tyrosine kinase related to the FLT1 and KDR/FLK1 vascular endothelial growth factor receptors. We have previously shown that FLT4 is expressed as transcripts of 4.5 and 5.8 kb in several human fetal and adult tissues. Here we show that these transcripts encode two polypeptides, FLT4s (short) and FLT41 (long), which are proteolytically processed in transfected cells and leukemia cells and which have different carboxy terminal tails. The 3' coding region of the 5.8 kb mRNA was found to be 65 codons longer than that of the the 4.5 kb mRNA. Analysis of the genomic structure of the region encoding the two carboxy termini revealed that the two transcripts are generated by alternative polyadenylation and subsequent alternative splicing during RNA processing. Our findings thus show regulation of FLT4 structure in the carboxy terminal tail considered important for receptor function. The significance of the two forms may relate to the role of additional potential autophosphorylation sites in the FLT4 long form.
Arja Kaipainen - One of the best experts on this subject based on the ideXlab platform.
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a novel vascular endothelial growth factor vegf c is a ligand for the FLT4 vegfr 3 and kdr vegfr 2 receptor tyrosine kinases
The EMBO Journal, 1996Co-Authors: Vladimir Joukov, Katri Pajusola, Arja Kaipainen, Dmitri Chilov, Isto Lahtinen, Eola Kukk, Olli Saksela, Nisse Kalkkinen, Kari AlitaloAbstract:Angiogenesis, the sprouting of new blood vessels from pre-existing ones, and the permeability of blood vessels are regulated by vascular endothelial growth factor (VEGF) via its two known receptors Flt1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2). The FLT4 receptor tyrosine kinase is related to the VEGF receptors, but does not bind VEGF and its expression becomes restricted mainly to lymphatic endothelia during development. In this study, we have purified the FLT4 ligand, VEGF-C, and cloned its cDNA from human prostatic carcinoma cells. While VEGF-C is homologous to other members of the VEGF/platelet derived growth factor (PDGF) family, its C-terminal half contains extra cysteine-rich motifs characteristic of a protein component of silk produced by the larval salivary glands of the midge, Chironomus tentans. VEGF-C is proteolytically processed, binds FLT4, which we rename as VEGFR-3 and induces tyrosine autophosphorylation of VEGFR-3 and VEGFR-2. In addition, VEGF-C stimulated the migration of bovine capillary endothelial cells in collagen gel. VEGF-C is thus a novel regulator of endothelia, and its effects may extend beyond the lymphatic system, where FLT4 is expressed.
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expression of the fms like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Arja Kaipainen, Daniel J Dumont, Jaana Korhonen, Tuija Mustonen, Victor W M Van Hinsbergh, Guohua Fang, Martin L Breitman, Kari AlitaloAbstract:We have recently cloned the human fms-like tyrosine kinase 4 gene FLT4, whose protein product is related to two vascular endothelial growth factor receptors FLT1 and KDR/FLK1. Here the expression of FLT4 has been analyzed by in situ hybridization during mouse embryogenesis and in adult human tissues. The FLT4 mRNA signals first became detectable in the angioblasts of head mesenchyme, the cardinal vein, and extraembryonally in the allantois of 8.5-day postcoitus (p.c.) embryos. In 12.5-day p.c. embryos, the FLT4 signal decorated developing venous and presumptive lymphatic endothelia, but arterial endothelia were negative. During later stages of development, FLT4 mRNA became restricted to vascular plexuses devoid of red cells, representing developing lymphatic vessels. Only the lymphatic endothelia and some high endothelial venules expressed FLT4 mRNA in adult human tissues. Increased expression occurred in lymphatic sinuses in metastatic lymph nodes and in lymphangioma. Our results suggest that FLT4 is a marker for lymphatic vessels and some high endothelial venules in human adult tissues. They also support the theory on the venous origin of lymphatic vessels.
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expression of endothelial cell specific receptor tyrosine kinases and growth factors in human brain tumors
American Journal of Pathology, 1995Co-Authors: Erika Hatva, Arja Kaipainen, P Mentula, Juha Jaaskelainen, Anders Paetau, Matti Haltia, Kari AlitaloAbstract:Abstract Key growth factor-receptor interactions involved in angiogenesis are possible targets for therapy of CNS tumors. Vascular endothelial growth factor (VEGF) is a highly specific endothelial cell mitogen that has been shown to stimulate angiogenesis, a requirement for solid tumor growth. The expression of VEGF, the closely related placental growth factor (PIGF), the newly cloned endothelial high affinity VEGF receptors KDR and FLT1, and the endothelial orphan receptors FLT4 and Tie were analyzed by in situ hybridization in normal human brain tissue and in the following CNS tumors: gliomas, grades II, III, IV; meningiomas, grades I and II; and melanoma metastases to the cerebrum. VEGF mRNA was up-regulated in the majority of low grade tumors studied and was highly expressed in cells of malignant gliomas. Significantly elevated levels of Tie, KDR, and FLT1 mRNAs, but not FLT4 mRNA, were observed in malignant tumor endothelia, as well as in endothelia of tissues directly adjacent to the tumor margin. In comparison, there was little or no receptor expression in normal brain vasculature. Our results are consistent with the hypothesis that these endothelial receptors are induced during tumor progression and may play a role in tumor angiogenesis.
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FLT4 FLT4 receptor ptk vertebrates
The Protein Kinase FactsBook#R##N#Protein-Serine Kinases, 1995Co-Authors: Katri Pajusola, Arja Kaipainen, Kari AlitaloAbstract:FLT4 is a PTK of the vascular endothelial growth factor (VEGF) (Flt1) receptor class. FLT4 does not bind VEGF, but a novel ligand instead. FLT4 is translated as a precursor form, which is proteolytically processed into an N-terminal subunit containing a major part of the extracellular domain, and a C-terminal subunit containing the transmembrane and intracellular regions. The subunits are held together by disulphide bonds. The FLT4 gene is expressed as two mRNAs (FLT4s and FLT4l) differing in their 3′ 2 coding sequences because of alternative polyadenylation and splicing. FLT4 shows the typical structure of receptor-type PTK, with a ligand-binding extracellular domain, a transmembrane domain, and an intracellular kinase domain with an insert region. The extracellular part comprises seven immunoglobulin homology domains with disulphide bonds.
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The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells.
The Journal of experimental medicine, 1993Co-Authors: Arja Kaipainen, Katri Pajusola, Olga Aprelikova, Jaana Korhonen, M G Persico, B I Terman, Kari AlitaloAbstract:The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.
Olga Aprelikova - One of the best experts on this subject based on the ideXlab platform.
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signalling properties of FLT4 a proteolytically processed receptor tyrosine kinase related to two vegf receptors
Oncogene, 1994Co-Authors: Katri Pajusola, Olga Aprelikova, Giuliana Pelicci, Herbert A Weich, Lena Claessonwelsh, Kari AlitaloAbstract:The FLT4, FLT1 and KDR/FLK1 genes encode structurally similar endothelial cell receptor tyrosine kinases. Recently it has been shown that the FLT1 and KDR/FLK-1 proteins function as high-affinity receptors for vascular endothelial growth factor (VEGF). Here we show that FLT4 does not act as a receptor for VEGF, as VEGF did not show specific binding to the FLT4 tyrosine kinase or induce its autophosphorylation. Also, FLT4 did not interact with KDR in response to VEGF. However, when fused with the ligand binding domain of the colony stimulating factor-1 receptor (CSF-1R), the FLT4 tyrosine kinase was specifically activated by CSF-1. The activated FLT4 tyrosine kinase domain was found to interact with the Src homology 2 domains of the SHC and GRB2 adaptor proteins in vitro and with SHC in cells. CSF-1 stimulation of the CSF-1R/FLT4 receptor chimera induced thymidine incorporation in serum-starved NIH3T3 fibroblasts, but not in porcine aortic or murine lung capillary endothelial cells, although tyrosyl phosphorylation of the receptor and SHC occurred in these cells as well. These results suggest that the endothelial cell FLT4 receptor tyrosine kinase transmits signals for an as yet unidentified growth factor.
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The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells.
The Journal of experimental medicine, 1993Co-Authors: Arja Kaipainen, Katri Pajusola, Olga Aprelikova, Jaana Korhonen, M G Persico, B I Terman, Kari AlitaloAbstract:The growth factor receptors expressed on endothelial cells are of special interest because of their potential to program endothelial cell growth and differentiation during development and neovascularization in various pathological states, such as wound healing and angiogenesis associated with tumorigenesis. Vascular endothelial growth factor ([VEGF] also known as vascular permeability factor) is a potent mitogen and permeability factor, which has been suggested to play a role in embryonic and tumor angiogenesis. The newly cloned FLT4 receptor tyrosine kinase gene encodes a protein related to the VEGF receptors FLT1 and KDR/FLK-1. We have here studied the expression of FLT4 and the other two members of this receptor family in human fetal tissues by Northern and in situ hybridization. These results were also compared with the sites of expression of VEGF and the related placenta growth factor (PlGF). Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs. A comparison of FLT4, FLT1 and KDR/FLK-1 receptor mRNA signals shows overlapping, but distinct expression patterns in the tissues studied. Certain endothelia lack one or two of the three receptor mRNAs. These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels.
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two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy terminal tails are produced by alternative processing of primary transcripts
Oncogene, 1993Co-Authors: Katri Pajusola, Olga Aprelikova, Elina Armstrong, S Morris, Kari AlitaloAbstract:Abstract FLT4 is a recently cloned gene encoding a transmembrane tyrosine kinase related to the FLT1 and KDR/FLK1 vascular endothelial growth factor receptors. We have previously shown that FLT4 is expressed as transcripts of 4.5 and 5.8 kb in several human fetal and adult tissues. Here we show that these transcripts encode two polypeptides, FLT4s (short) and FLT41 (long), which are proteolytically processed in transfected cells and leukemia cells and which have different carboxy terminal tails. The 3' coding region of the 5.8 kb mRNA was found to be 65 codons longer than that of the the 4.5 kb mRNA. Analysis of the genomic structure of the region encoding the two carboxy termini revealed that the two transcripts are generated by alternative polyadenylation and subsequent alternative splicing during RNA processing. Our findings thus show regulation of FLT4 structure in the carboxy terminal tail considered important for receptor function. The significance of the two forms may relate to the role of additional potential autophosphorylation sites in the FLT4 long form.
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FLT4 receptor tyrosine kinase gene mapping to chromosome band 5q35 in relation to the t 2 5 t 5 6 and t 3 5 translocations
Genes Chromosomes and Cancer, 1993Co-Authors: Elina Armstrong, Kari Alitalo, Olga Aprelikova, John J Wasmuth, Kumar Kastury, Florencia Bullrich, Christian Nezelof, Jean Gogusev, Steven Morris, Kay HuebnerAbstract:FLT4 is a recently cloned receptor tyrosine kinase cDNA, which is characterized by seven immunoglobulin-like loops in its extracellular domain. We have previously mapped the FLT4 gene to chromosome segment 5q33-qter using somatic cell hybrids. Here we have refined the localization to band 5q35 by fluorescence in situ hybridization and show that the gene is translocated to chromosomes 2 and 6 in the t(2;5)(p23;q35) and t(5;6)(q35;p21) translocations, respectively, of Ki-1-positive lymphomas, as well as to chromosome 3 in the t(3;5)(q25.1;q34) translocation, which is occasionally found in myelodysplastic syndromes and acute myeloid leukemia. No evidence was obtained for a rearrangement or deregulation of the translocated FLT4 gene. We further show that abundant FLT4 mRNA expression occurs only in erythroid and megakaryoblastoid cell lines among nine leukemia cell lines studied. © 1993 Wiley-Liss, Inc.
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FLT4 receptor tyrosine kinase contains seven immunoglobulin like loops and is expressed in multiple human tissues and cell lines
Cancer Research, 1992Co-Authors: Katri Pajusola, Olga Aprelikova, Arja Kaipainen, Jaana Korhonen, Riitta Alitalo, Liisa Pertovaara, Kari AlitaloAbstract: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.
Daniel Birnbaum - One of the best experts on this subject based on the ideXlab platform.
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les recepteurs pour les facteurs de la famille du vegf
Bulletin Du Cancer, 1997Co-Authors: Emmanuel Fournier, Daniel Birnbaum, Jeanpaul BorgAbstract:Les facteurs de croissance de la famille VEGF (vascular endothelial growth factor), dont 4 sont bien caracterises, sont consideres comme des acteurs essentiels de la biologie des vaisseaux sanguins. Leurs recepteurs de haute affinite sont des molecules transmembranaires dotees d’une activite tyrosine kinase. Ces recepteurs sont au nombre de 3 (FLT1 ou VEGFR1, FLK1/KDR ou VEGFR2, et FLT4 ou VEGFR3). Les interactions VEGF/VEGFR ont un role capital dans la formation de vaisseaux sanguins au cours du developpement et de la vie adulte, dans certaines circonstances bien definies, mais aussi lors de certaines pathologies impliquant une neovascularisation comme la croissance tumorale.
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mutation at tyrosine residue 1337 abrogates ligand dependent transforming capacity of the FLT4 receptor
Oncogene, 1995Co-Authors: Emmanuel Fournier, Daniel Birnbaum, Patrice Dubreuil, Jeanpaul BorgAbstract:In humans, the FLT4 gene encodes two isoforms of a tyrosine kinase receptor, which differ in their carboxy terminal regions. As compared to the short form, the long form has an additional stretch of 65 amino acids containing three tyrosine residues (Y1333, Y1337 and Y1363). Once expressed in fibroblast cells, only the long form is able to elicit both anchorage-independent growth in a soft agar assay and tumors in nude mice, and thus appears endowed with a potential ligand-dependent transforming capacity. Replacement of tyrosine 1337 by phenylalanine abrogates the transforming capacity of the long form. This residue was identified as a potential autophosphorylation site, and a docking site for a substrate important in the signal transduction specific of the long FLT4 isoform. We demonstrate that the GRB2 and SHC cytoplasmic substrates are involved in FLT4 signal transduction. SHC interaction could be crucial to FLT4-mediated transforming activity associated with the long isoform. Finally, trancripts for the two forms are detected in tissues positive for FLT4 gene expression.
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biochemical characterization of two isoforms of FLT4 a vegf receptor related tyrosine kinase
Oncogene, 1995Co-Authors: Jeanpaul Borg, Patrice Dubreuil, Robert Rottapel, Odile Delapeyriere, Tetsuro Noguchi, Daniel BirnbaumAbstract:The FLT4 gene encodes a tyrosine kinase receptor related to the two identified receptors for vascular endothelial growth factor (VEGF), FLT1 and FLK1/KDR. Two isoforms of FLT4, differing by their C-terminal ends, have been identified. The long form has 65 additional amino acid residues. We have shown that FLT4 is a highly glycosylated, relatively stable, cell surface associated kinase of approximately 180 kDa. In order to study the signal transduction molecules associated with the FLT4 pathway, and in the absence of a known ligand, we constructed two chimeric molecules (FF4S and FF4L) made of the extracellular region of the CSF1 receptor (Fms gene product) and of the transmembrane and intracellular regions of either form of FLT4. These two chimeric forms were expressed in Rat 2 transfectants. We assayed the ligand-induced capacity of the FF4 short and long forms to sustain growth of Rat 2 cells in semisolid medium. In a soft agar assay, only the long form was able to induce the growth of Rat 2 cells upon ligand treatment. The two forms of FLT4 therefore have different functional capacities. We looked for association and/or phosphorylation of phospholipase C gamma (PLC gamma) and phosphatidylinositol-3'-phosphate (PI3K), after stimulation of the FF4 molecules by CSF1. Finally, we have studied the expression of the FLT4 gene in mouse embryos and in the adult by in situ hybridization. FLT4 transcripts were found at day 12.5 post-coitum and thereafter, including the adult mouse, predominantly in the pericardium, pleural membranes and in the lung.
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Characterization of a yeast artificial chromosome from human chromosome band 13q12 containing the FLT1 and FLT3 receptor-type tyrosine kinase genes
Cytogenetics and Cell Genetics, 1994Co-Authors: Aurélia Imbert, Daniel Birnbaum, Olivier Rosnet, Sylvie Marchetto, Vincent Ollendorff, Marie-josephe PébusqueAbstract:A yeast artificial chromosome containing the two receptor-type tyrosine kinase genes FLT1 and FLT3 was isolated, analyzed, and compared to a genomic map in order to establish their organization and linkage. FLT1 and FLT3 are physically linked in a head-to-tail configuration and separated by about 150 kb. The region contains three CpG islands. Two of them are likely to correspond to FLT1 and FLT3, whereas the third one is suggestive of another putative, unidentified RTK gene.
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the FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor
Oncogene, 1993Co-Authors: Franck Galland, Patrice Dubreuil, Jeanpaul Borg, Olivier Rosnet, Marie-josephe Pébusque, Aida Karamysheva, Robert Rottapel, Daniel BirnbaumAbstract:Abstract Three receptor tyrosine kinases, FLT1, FLK1 and FLT4, contain seven immunoglobin-like domains in their extracellular region and are strongly related by sequence similarities to each other and, to a lesser degree, to the class III receptors CSF1R/FMS, PDGFR, SLFR/KIT and FLT3/FLK2. They constitute a family of receptors putatively involved in the growth regulation of endothelial cells. We describe here the structure and pattern of expression of the human FLT4 gene. Two FLT4 transcripts of 5.8 and 4.5 kb are expressed in the human placenta and several hematopoietic cell lines. In mouse, a 5.8-kb transcript is expressed in a variety of tissues. A translational product 1298 amino acids in length is predicted to be encoded by the largest open reading frame. The FLT4 protein, when transiently expressed in Cos-7 cells and immunoprecipitated with a FLT4-specific rabbit immune serum, has an apparent molecular weight of 170 kDa.