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FLT4

Official Full Name
fms related receptor tyrosine kinase 4
Organism
Homo sapiens
GeneID
2324
Background
This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]
Synonyms
PCL; CHTD7; FLT-4; FLT41; LMPH1A; LMPHM1; VEGFR3; VEGFR-3;
Bio Chemical Class
Kinase
Protein Sequence
MQRGAALCLRLWLCLGLLDGLVSGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNVPPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQDLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHDAHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSMEIVILVGTGVIAVFFWVLLLLIFCNMRRPAHADIKTGYLSIIMDPGEVPLEEQCEYLSYDASQWEFPRERLHLGRVLGYGAFGKVVEASAFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKILIHIGNHLNVVNLLGACTKPQGPLMVIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRFRAMVELARLDRRRPGSSDRVLFARFSKTEGGARRASPDQEAEDLWLSPLTMEDLVCYSFQVARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLARDIYKDPDYVRKGSARLPLKWMAPESIFDKVYTTQSDVWSFGVLLWEIFSLGASPYPGVQINEEFCQRLRDGTRMRAPELATPAIRRIMLNCWSGDPKARPAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQSSEEGSFSQVSTMALHIAQADAEDSPPSLQRHSLAARYYNWVSFPGCLARGAETRGSSRMKTFEEFPMTPTTYKGSVDNQTDSGMVLASEEFEQIESRHRQESGFSCKGPGQNVAVTRAHPDSQGRRRRPERGARGGQVFYNSEYGELSEPSEEDHCSPSARVTFFTDNSY
Open
Disease
Alzheimer disease, Breast cancer, Circulatory system disease, Liver cancer, Lung cancer, Prostate cancer, Renal cell carcinoma, Solid tumour/cancer, Stomach cancer
Approved Drug
1 +
Clinical Trial Drug
11 +
Discontinued Drug
0

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Detailed Information

The FLT4 gene, also known as VEGFR-3 (Vascular Endothelial Growth Factor Receptor-3), encodes a tyrosine kinase receptor that plays a crucial role in regulating lymphangiogenesis, and the formation of lymphatic vessels. This receptor is primarily involved in the development of the lymphatic system and the maintenance of its endothelium. Mutations in FLT4 can result in various diseases, most notably hereditary lymphedema type IA, a condition characterized by swelling, typically in the limbs, due to impaired lymphatic function. The gene also plays a part in the cardiovascular system's development during embryogenesis.

In this article, we explore the significance of FLT4 in both normal physiology and disease processes, focusing on its role in lymphatic development, signaling pathways, and associated mutations that lead to disorders like Milroy disease and lymphedema. Understanding the various aspects of FLT4 can aid in developing targeted therapies for lymphatic-related disorders and shed light on its broader implications in vascular biology.

FLT4 and Its Role in Lymphatic Development

FLT4 is part of the tyrosine kinase receptor family, specifically acting as a receptor for the vascular endothelial growth factors VEGF-C and VEGF-D. The formation of lymphatic vessels depends on these growth factors, hence FLT4's activation by VEGF-C and VEGF-D sets off a sequence of intracellular signaling pathways supporting lymphatic endothelial cell survival, migration, and expansion.

The function of the receptor is crucial in both embryonic and adult lymphangiogenesis. Beginning as early as day 8.5 of development, FLT4 is active in the creation of the first lymphatic vessels in embryos. Its importance in building a functional lymphatic system is great since mutations in FLT4 can cause lymphatic vessel development to fail and perhaps cause embryonic mortality in animal models. Particularly during wound healing, inflammation, and tumor development, FLT4 is still important in adults for the upkeep and growth of the lymphatic system.

The complex signaling systems of FLT4 consist of several downstream pathways, including PI3K-Akt pathways and the MAPK (mitogen-activated protein kinase). Important for creating and preserving the lymphatic vasculature, these routes control cell proliferation, migration, and survival. Furthermore modifying relationships with other vascular receptors, such as VEGFR-2, and FLT4 adds to the intricacy of lymphatic and vascular development.

Mutations in FLT4 and Their Impact

Mutations in FLT4 can lead to a variety of disorders, most notably Milroy disease (MD), a hereditary form of primary lymphedema. Usually starting with swelling in the lower limbs soon after birth, Milroy's illness is defined by congenital lymphedema. Mutations in the FLT4 gene that compromise its tyrosine kinase activity cause the disorder, therefore influencing lymphatic development and producing faulty lymphatic vessel creation.

Because FLT4 is produced in the lymphatic endothelium, mutations in this gene throw off the usual signaling needed for lymphatic artery formation. With over 50 variants found—missense mutations, deletions, and splicing variants—a study of clinical data suggests that most instances of Milroy illness are associated with mutations in FLT4. Usually affecting the tyrosine kinase regions of the receptor, these mutations cause either reduced kinase activity or defective receptor phosphorylation—qualities required for appropriate lymphatic artery development.

The variety in the clinical presentation of Milroy's illness reflects different expressions of the mutations and insufficient penetrance. While some people show very moderate symptoms, others could suffer from severe edema and consequences including cellulitis and skin infections. Moreover, asymptomatic bearers of FLT4 mutations have been documented, therefore illustrating the genetic complexity of the disorder.

Apart from Milroy syndrome, FLT4 mutations have been linked to other disorders including congenital cardiac problems and lymphatic abnormalities. These disorders emphasize the larger function of the gene in vascular health since they are related to inappropriate lymphatic development or vascular remodeling.

FLT4 in Immune Response and Infections

Recent studies have revealed an intriguing aspect of FLT4's role in immune cell function, particularly in macrophages. During bacterial infections, macrophages activate FLT4 and its ligand VEGF-C; FLT4 signaling is therefore essential in controlling inflammation and immunological reactions. Specifically, FLT4 has been demonstrated to promote autophagy—a cellular mechanism that helps eradicate pathogens—while suppressing the activation of inflammasomes, complexes engaged in inflammatory processes.

Under infection, FLT4 gathers the enzyme AMP-activated protein kinase (AMPK), which controls cellular metabolism. This link between FLT4 and AMPK guarantees correct glycolytic reprogramming in macrophages, therefore enabling their defense against bacterial infections. Research in Flt4 mutant mice has revealed that loss of FLT4 activity results in altered glycolytic metabolism and higher generation of proinflammatory chemicals, therefore compromising the immune response.

Figure 1 illustrates the FLT4-AMPK signaling pathway in macrophages, showing how it regulates glycolytic metabolism, autophagy, inflammasome activation, and pyroptosis to enhance bacterial infection resistance.Figure 1. The FLT4-AMPK module regulates macrophage glycolytic metabolism to coordinate autophagy, inflammasome activation, and pyroptosis, enhancing immune defense against bacterial infection. (Ma L, et al., 2022)

These findings open new avenues for therapeutic strategies targeting FLT4 signaling to improve immune function, especially in individuals with mutations in FLT4 that predispose them to recurrent infections. This is particularly relevant for patients with hereditary lymphedema or other FLT4-related disorders, as enhancing immune responses could potentially mitigate some of the chronic infections that often accompany these conditions.

Therapeutic Implications and Future Directions

Therapeutic possibilities abound from the continuous research on the function of FLT4 in lymphangiogenesis and immunological control. Restoring normal FLT4 signaling may assist in correcting lymphatic vessel growth and reduce lymphedema symptoms in disorders such as Milroy disease, where FLT4 mutations cause lymphatic malfunction. Treating hereditary lymphedema and other vascular abnormalities may find use for gene therapy or small compounds enhancing FLT4 signaling.

Moreover, the immune-modulating action of FLT4 in macrophages offers still another therapeutic target. In the framework of infections, adjusting FLT4 signaling could help individuals with FLT4 mutations who are prone to repeated infections have more immunological responses. In cancer, where FLT4 is involved in tumor lymphangiogenesis and metastases, pharmacological treatments meant to modulate FLT4 activity could also have advantages.

References:

  1. Gordon K, Spiden SL, et al. FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update. Hum Mutat. 2013 Jan;34(1):23-31.
  2. Melincovici CS, Boşca AB, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59(2):455-467.
  3. Ma L, Li W, Zhang Y, et al. FLT4/VEGFR3 activates AMPK to coordinate glycometabolic reprogramming with autophagy and inflammasome activation for bacterial elimination. Autophagy. 2022;18(6):1385-1400.
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