FLT1

Official Full Name

fms related receptor tyrosine kinase 1

Organism

Homo sapiens

GeneID

2321

Background

This gene encodes a member of the vascular endothelial growth factor receptor (VEGFR) family. VEGFR family members are receptor tyrosine kinases (RTKs) which contain an extracellular ligand-binding region with seven immunoglobulin (Ig)-like domains, a transmembrane segment, and a tyrosine kinase (TK) domain within the cytoplasmic domain. This protein binds to VEGFR-A, VEGFR-B and placental growth factor and plays an important role in angiogenesis and vasculogenesis. Expression of this receptor is found in vascular endothelial cells, placental trophoblast cells and peripheral blood monocytes. Multiple transcript variants encoding different isoforms have been found for this gene. Isoforms include a full-length transmembrane receptor isoform and shortened, soluble isoforms. The soluble isoforms are associated with the onset of pre-eclampsia.[provided by RefSeq, May 2009]

Synonyms

FLT; FLT-1; VEGFR1; VEGFR-1;

Bio Chemical Class

Kinase

Protein Sequence

MVSYWDTGVLLCALLSCLLLTGSSSGSKLKDPELSLKGTQHIMQAGQTLHLQCRGEAAHKWSLPEMVSKESERLSITKSACGRNGKQFCSTLTLNTAQANHTGFYSCKYLAVPTSKKKETESAIYIFISDTGRPFVEMYSEIPEIIHMTEGRELVIPCRVTSPNITVTLKKFPLDTLIPDGKRIIWDSRKGFIISNATYKEIGLLTCEATVNGHLYKTNYLTHRQTNTIIDVQISTPRPVKLLRGHTLVLNCTATTPLNTRVQMTWSYPDEKNKRASVRRRIDQSNSHANIFYSVLTIDKMQNKDKGLYTCRVRSGPSFKSVNTSVHIYDKAFITVKHRKQQVLETVAGKRSYRLSMKVKAFPSPEVVWLKDGLPATEKSARYLTRGYSLIIKDVTEEDAGNYTILLSIKQSNVFKNLTATLIVNVKPQIYEKAVSSFPDPALYPLGSRQILTCTAYGIPQPTIKWFWHPCNHNHSEARCDFCSNNEESFILDADSNMGNRIESITQRMAIIEGKNKMASTLVVADSRISGIYICIASNKVGTVGRNISFYITDVPNGFHVNLEKMPTEGEDLKLSCTVNKFLYRDVTWILLRTVNNRTMHYSISKQKMAITKEHSITLNLTIMNVSLQDSGTYACRARNVYTGEEILQKKEITIRDQEAPYLLRNLSDHTVAISSSTTLDCHANGVPEPQITWFKNNHKIQQEPGIILGPGSSTLFIERVTEEDEGVYHCKATNQKGSVESSAYLTVQGTSDKSNLELITLTCTCVAATLFWLLLTLFIRKMKRSSSEIKTDYLSIIMDPDEVPLDEQCERLPYDASKWEFARERLKLGKSLGRGAFGKVVQASAFGIKKSPTCRTVAVKMLKEGATASEYKALMTELKILTHIGHHLNVVNLLGACTKQGGPLMVIVEYCKYGNLSNYLKSKRDLFFLNKDAALHMEPKKEKMEPGLEQGKKPRLDSVTSSESFASSGFQEDKSLSDVEEEEDSDGFYKEPITMEDLISYSFQVARGMEFLSSRKCIHRDLAARNILLSENNVVKICDFGLARDIYKNPDYVRKGDTRLPLKWMAPESIFDKIYSTKSDVWSYGVLLWEIFSLGGSPYPGVQMDEDFCSRLREGMRMRAPEYSTPEIYQIMLDCWHRDPKERPRFAELVEKLGDLLQANVQQDGKDYIPINAILTGNSGFTYSTPAFSEDFFKESISAPKFNSGSSDDVRYVNAFKFMSLERIKTFEELLPNATSMFDDYQGDSSTLLASPMLKRFTWTDSKPKASLKIDLRVTSKSKESGLSDVSRPSFCHSSCGHVSEGKRRFTYDHAELERKIACCSPPPDYNSVVLYSTPPI

Open

Disease

Arterial occlusive disease, Bladder cancer, Chronic arterial occlusive disease, Colorectal cancer, Diabetic foot ulcer, Macular degeneration, Pancreatic cancer, Renal cell carcinoma, Retinopathy, Solid tumour/cancer, Stomach cancer

Approved Drug

2 +

Clinical Trial Drug

12 +

Discontinued Drug

2 +

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Detailed Information

Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial physiological process essential for normal development, wound healing, and tissue repair. The vascular endothelial growth factor (VEGF) family—including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor—regulates the process mainly. Among other vascular-associated cells, including vascular endothelial growth factor receptors (VEGFRs), these elements interact with certain receptors on endothelial cells (ECs). Angiogenesis, vascular permeability, and tissue-specific responses are regulated in major part by VEGFR1, a receptor tyrosine kinase (RTK). The several roles of VEGFR1, its signaling pathways, and their possible therapeutic consequences in vascular illnesses and disorders including diabetic retinopathy, age-related macular degeneration, and cancer are investigated in this study.

VEGFR1 Structure and Function

Comprising an external ligand-binding domain, a single transmembrane segment, and an intracellular tyrosine kinase domain, the VEGFR1 gene codes a member of the VEGFR family. Like other receptor tyrosine kinases (RTKs), Seven immunoglobulins (Ig)-like domains found in VEGFR1's extracellular component help to mediate its interaction with ligands including VEGF-A, VEGF-B, and PlGF. VEGFR1 can set off several signaling cascades influencing endothelial cell activity including migration, proliferation, and survival upon interaction of these ligands.

Fascinatingly, VEGFR1 boasts two main isoforms: a soluble version (sVEGFR1) and a full-length membrane-bound receptor. Lack of a transmembrane domain, the soluble isoform binds VEGF-A to operate as a decoy receptor, therefore blocking its interaction with another important receptor engaged in angiogenesis: VEGFR2. Maintaining vascular homeostasis and control of VEGF-A depend on this decoy action of VEGFR1. Soluble VEGFR1 has been linked to disorders like pre-eclampsia, where it might cause pathogenic changes in vascular flow.

Apart from its function in angiogenesis, VEGFR1 is also rather important for the control of immune cells. It is expressed not just in endothelial cells but also in several immune cells including monocytes, macrophages, and microglia. This general expression profile implies that VEGFR1 controls immunological responses, vascular permeability, and inflammation.

This figure has summarized the current understanding of VEGFR1 in the regulation of angiogenesis, immune response, and vascular permeability. Figure 1. Schematic representation of VEGFR1 in the choroid and retina and VEGFR1 signaling. (Uemura A, et al., 2021)

VEGFR1 in Angiogenesis and Vascular Pathophysiology

Angiogenesis is a highly regulated process that involves the coordinated activation of endothelial cells. The complicated and varied role VEGFR1 plays in angiogenesis depends on the cellular environment and the particular ligands engaged. The most often investigated ligand of VEGFR1, VEGF-A binds to VEGFR1 and VEGFR2 both of which activate different signaling pathways. VEGFR2 is the main receptor in endothelial cells that mediates the pro-angiogenic effects of VEGF-A including new blood vessel development, migration, and enhanced endothelial cell proliferation. Using its decoy action, VEGFR1 acts as a negative regulator of VEGF-A signaling, therefore preventing the too-rapid proliferation of endothelial cells and guaranteeing controlled angiogenesis.

Because VEGFR1 is involved in retinal illnesses including diabetic retinopathy (DR) and age-related macular degeneration (AMD), its function in the retina has attracted major interest. Unusual angiogenesis and vascular permeability define both diseases and cause vision loss. Inside DR, alterations in vascular integrity inside the inner retina cause edema, bleeding, and neovascularization. Retinal endothelial cells, pericytes, and macrophages all express VEGFR1; its activation can affect vascular permeability and inflammatory responses inside the retina. Maintaining retinal function depends on a balance between pathological and physiological angiogenesis, which is regulated in part by VEGFR1's capacity as a decoy receptor for VEGF-A.

Likewise in AMD, especially the wet variety (neovascular AMD), aberrant choroidal neovascularization (CNV) results from ongoing VEGF-A signal. Here, by reducing too strong VEGF-A-induced angiogenesis, VEGFR1 could play a protective role. Further study is required to clarify how VEGFR1 contributes to various disorders since the balance between VEGFR1 decoy activity and direct signaling remains complicated and depends on the context.

Therapeutic Implications of VEGFR1

VEGFR1 has become a major therapeutic target in several disorders marked by aberrant blood vessel development given its function in angiogenesis and vascular permeability. In the setting of cancer, where angiogenesis commonly drives tumor development, inhibiting VEGF signaling by VEGFR1 and VEGFR2 inhibitors shows promise in clinical trials. By preventing VEGF-A binding to its receptors, anti-VEGF treatments—including bevacizumab (Avastin)—are extensively utilized to treat malignancies, therefore restricting metastatic dissemination and lowering tumor-associated blood vessel formation.

Anti-VEGF treatments have transformed therapy approaches in retinal illnesses like age-related macular degeneration and diabetic retinopathy. Drugs such as ranibizumab and aflibercept target VEGF-A and, to some degree, VEGF-B, and PlGF, therefore lowering retinal neovascularization and macular edema. Although these treatments mostly target VEGFR2 signaling, the involvement of VEGFR1 in controlling VEGF-A availability and receptor binding implies that directly targeting VEGFR1, or altering its decoy function, may offer another layer of therapeutic benefit.

Moreover, under investigation is the medicinal application of soluble VEGFR1. Increasing soluble VEGFR1 levels in the circulation could help to sequester VEGF-A and reduce its pro-angiogenic properties in disorders marked by aberrant vascular development. Furthermore, the targeted suppression of VEGFR1 signaling in immune cells like macrophages and microglia can provide fresh approaches for treating inflammatory diseases related to angiogenesis.

References:

Uemura A, Fruttiger M, et al. VEGFR1 signaling in retinal angiogenesis and microinflammation. Prog Retin Eye Res. 2021 Sep;84:100954.
Ferrara N, Gerber HP, et al. The biology of VEGF and its receptors. Nat Med. 2003 Jun;9(6):669-76.

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