Disease relevance of FLT4

• To characterize the signaling events after VRP engagement of its cognate receptor in hematopoietic cells, a population of human erythroleukemia (HEL) cells, termed HEL-JW, expressing high levels of FLT4 receptor was isolated [1].
• Interestingly, a Wilms' tumor cell line, a retinoblastoma cell line, and a nondifferentiated teratocarcinoma cell line expressed FLT4, whereas differentiated teratocarcinoma cells were negative [2].
• We have analyzed the expression of VEGF and its receptors, the related placental growth factor (PlGF) and the endothelial receptors FLT4 and Tie by in situ hybridization in capillary hemangioblastomas and hemangiopericytomas [3].
• Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus [4].
• Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia [5].

Psychiatry related information on FLT4

• A limit for MPEG initiator esterification in lipase-catalyzed CL polymerization was observed and was explained by preferential reaction of PCL propagation over MPEG esterification at long reaction times and low MPEG concentrations [6].
• The patients were assessed using the Posttraumatic Stress Disorder Checklist (PCL), the General Health Questionnaire-28 (GHQ-28) and the Multidimensional Health Locus of Control (MHLC) [7].
• The questionnaire included the General Health Questionnaire (GHQ-12), the post-traumatic stress disorder checklist (PCL), 15 symptoms and an assessment of alcohol intake [8].
• During the first 6 months post-discharge, after controlling for the presence of antisocial personality disorder or PCL score and past diagnoses of alcohol/drug abuse/dependence, the presence of a severe positive symptom significantly increased the risk of aggressive behavior [9].

High impact information on FLT4

• Two of its family members, VEGF-C and VEGF-D, regulate the lymphatic endothelial cells via their receptor VEGFR-3 [10].
• Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema [11].
• Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema [11].
• Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting (dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants [12].
• VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively [13].

Chemical compound and disease context of FLT4

• Recent studies have shown that missense mutations within the VEGFR-3 tyrosine kinase domain are associated with human hereditary lymphedema, suggesting an important role for this receptor in the development of the lymphatic vasculature [14].
• The association between the NH(2) terminus of VEGFR-3, containing the peptide identified by phage display, and the COOH terminus of FAK was detected by in vitro and in vivo binding studies [15].
• Interestingly, phototoxicity of control liposomal BPD-MA was suppressed in the presence of serum, but PCL maintained the phototoxicity in the presence of serum following PCL-mediated PDT treatment due to the stability of PCL and the reduced detachment of encapsulated photosensitizer from liposome to serum [16].
• Four different immobilized lipases were tested, Candida antarctica type B (CALB), Rhizomucor miehei (RML), Pseudomonas cepacia (PCL), and Penicillium roquefortii (PRL). n-Hexane and diisopropyl ether (DIPE) were examined as reaction media at three different water activities (a(w)), 0.11, 0.53, and 0.97 [17].
• The lipase from Pseudomonas cepacia (PCL) showed the highest (S)-enantioselectivity (E > 100), and cyclohexane containing 1% (v/v) buffer was identified as the best reaction medium for maintaining high enantioselectivity as well as high reaction rate [18].

Biological context of FLT4

• VRP induced tyrosine phosphorylation of various proteins, including the FLT4 receptor [1].
• Signal transduction in human hematopoietic cells by vascular endothelial growth factor related protein, a novel ligand for the FLT4 receptor [1].
• The extracellular domain of FLT4 consists of 7 immunoglobulin-like loops, including 12 potential glycosylation sites [2].
• Finally, trancripts for the two forms are detected in tissues positive for FLT4 gene expression [19].
• Soft agar assay experiments revealed that the VEGFR3/FLT4 transforming capacity is increased by the mutation of Y239/Y240 to phenylalanines in SHC, suggesting that these two residues mediate an inhibitory signal for cell growth [20].

Anatomical context of FLT4

• Our results reveal FLT4 mRNA expression in vascular endothelial cells in developing vessels of several organs [21].
• 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 [21].
• No evidence was obtained for the expression of FLT4 in the endothelial cells of blood vessels [2].
• FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines [2].
• In in situ hybridization the FLT4 autoradiographic grains decorated bronchial epithelial cells of fetal lung [2].

Associations of FLT4 with chemical compounds

• Further characterization of these tyrosine phosphorylated molecules revealed that Shc, Grb2, and SOS form a complex with the activated FLT4 receptor [1].
• 0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family [22].
• Dexamethasone did not affect VEGFR-3 gene expression in vitro and in vivo [23].
• VEGF-A, but not glucose alone, stimulated VEGFR-3 mRNA expression [24].
• 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 [25].

Physical interactions of FLT4

• Another tyrosine kinase receptor, VEGFR-3 (flt-4) binds VEGF-C and VEGF-D and is more important in the development of lymphatic vessels [26].
• Here we report that VEGFR-3 localizes in the caveolae membrane of endothelial cells and co-immunoprecipitates with caveolin-1 [27].
• NP2 also interacted with VEGFR-3 in coprecipitation studies [28].

Co-localisations of FLT4

• VEGF receptor 1 and 2 as well as blood vessel endothelial and basal lamina markers were colocalized with VEGFR-3 in many of these vessels [29].

Regulatory relationships of FLT4

• Surprisingly, immunoprecipitation studies detected no VEGF-C-induced autophosphorylation of VEGF-R3 in hCIPs but did so in HMVECs [30].
• Full-length VEGF-C and VEGF-D induced predominantly and the selective VEGFR-3 ligand VEGF-C156S exclusively lymphangiogenesis [31].
• Using western blotting we could demonstrate that interleukin-1 beta (IL-1 beta) stimulates the expression of VEGFR-3 in chondrocytes in vitro in a dose-dependent manner [32].
• These findings were confirmed in vitro using human LECs and anti-human antagonist mAbs (IMC-1121a and hF4-3C5): both VEGFR-2 and -3 signaling were required for migration and proliferation, but tubulogenesis in 3D cultures was unaffected by VEGFR-3 blocking and partially hindered by VEGFR-2 blocking [33].
• The results showed that VEGF-C and VEGFR-3 were highly expressed in cytoplasm and membrane in lung cancer tissues with the positive rate being 55.4 % and 52.3 % respectively, while there was no expression in the normal lung tissues [34].

Other interactions of FLT4

• Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4 [35].
• Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy [36].
• The fms-like tyrosine kinase 4 (FLT4) complementary DNA was cloned from a human HEL erythroleukemia cell library by polymerase chain reaction-amplification [2].
• Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites [37].
• Biosensor analysis demonstrated that the VHD has approximately 290- and approximately 40-fold greater affinity for VEGFR-2 and VEGFR-3, respectively, compared with unprocessed VEGF-D [38].

Analytical, diagnostic and therapeutic context of FLT4

• FLT4 expression was confirmed by immunocytochemistry in a subgroup of the studied patient population [5].
• Using a sensitive PCR method we detected FLT4 m-RNA in 15 of 41 patients with de novo AML at diagnosis or relapse and in three of 12 patients with secondary AML [5].
• Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor [39].
• The survival rates of patients with positive staining for tumor-cell and endothelial-cell VEGFR-3 were significantly lower than those with negative staining (P = 0.0034 and P = 0.0020, respectively) [40].
• Patients with positive staining for both tumor-cell VEGF-C and endothelial-cell VEGFR-3 exhibited the most unfavorable prognoses [40].

References