FGFR4

Official Full Name

fibroblast growth factor receptor 4

Organism

Homo sapiens

GeneID

2264

Background

The protein encoded by this gene is a tyrosine kinase and cell surface receptor for fibroblast growth factors. The encoded protein is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. This protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. [provided by RefSeq, Aug 2017]

Synonyms

TKF; JTK2; CD334;

Bio Chemical Class

mRNA target

Protein Sequence

MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTAAAPEARYTDIILYASGSLALAVLLLLAGLYRGQALHGRHPRPPATVQKLSRFPLARQFSLESGSSGKSSSSLVRGVRLSSSGPALLAGLVSLDLPLDPLWEFPRDRLVLGKPLGEGCFGQVVRAEAFGMDPARPDQASTVAVKMLKDNASDKDLADLVSEMEVMKLIGRHKNIINLLGVCTQEGPLYVIVECAAKGNLREFLRARRPPGPDLSPDGPRSSEGPLSFPVLVSCAYQVARGMQYLESRKCIHRDLAARNVLVTEDNVMKIADFGLARGVHHIDYYKKTSNGRLPVKWMAPEALFDRVYTHQSDVWSFGILLWEIFTLGGSPYPGIPVEELFSLLREGHRMDRPPHCPPELYGLMRECWHAAPSQRPTFKQLVEALDKVLLAVSEEYLDLRLTFGPYSPSGGDASSTCSSSDSVFSHDPLPLGSSSFPFGSGVQT

Open

Disease

Liver cancer, Obesity, Retina cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

1 +

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Detailed Information

Fibroblast Growth Factor Receptor 4 (FGFR4) is a critical cell-surface receptor with tyrosine kinase activity, which plays a significant role in regulating cell proliferation, differentiation, migration, and metabolism.

It is part of various physiological processes including vitamin D metabolism, bile acid production, glucose absorption, and lipid metabolism. Highly precise interactions between this protein and its ligand, Fibroblast Growth Factor 19 (FGF19) result in receptor dimerization and activation of downstream signaling paths. These pathways comprise the PI3K/AKT, MAPK, and GSK3β/β-catenin signaling cascades, which taken together affect several cellular reactions including growth, survival, and epithelial-mesenchymal transition (EMT). Several illnesses, including pancreatic cancer and liver cancer (HCC), have been associated with either normal activation or deficient inactivation of FGFR4.

FGFR4 and Its Mechanisms of Action

FGFR4 is a member of a family of receptor tyrosine kinases (RTKs), which dimerize and activate their intracellular kinase domains upon ligand engagement. Regarding FGFR4, its ligand, FGF19, interacts with a co-receptor β-Klotho to create a ternary complex starting receptor autophosphorylation. FGF receptor substrate 2 (FRS2), among other intracellular signaling proteins, is triggered by this phosphorylation event to recruit other signaling molecules including GRB2, PI3K, and SOS1, therefore regulating cell survival and growth.

The PI3K/AKT pathway, which advances cell growth and survival, is one of the main downstream consequences of offgFR4 activation. Furthermore engaged in cell differentiation, migration, and immunological responses are the RAS/MAPK and PLCγ/DAG/PKC paths, which FGFR4 signaling also activates. By modulating CYP7A1, the rate-limiting enzyme in bile acid synthesis, FGFR4 is essential in liver cells for regulating bile acid synthesis. Liver homeostasis depends much on the disruption of FGFR4 signaling, which is associated with liver diseases including hepatocellular carcinoma (HCC).

FGFR4 in Cancer: Mechanisms of Tumorigenesis

Because of its significance in tumorigenesis—especially in liver cancer—fgFR4 has attracted a lot of interest in the setting of cancer. Enhancing tumor cell proliferation, EMT, and resistance to death using FGF19's overexpression and binding to FGFR4 has been linked to driving cancer progression. This signaling axis helps malignant cells in liver cancer grow and spread, hence FGFR4 is a possible therapeutic target.

Particularly in hepatocellular carcinoma (HCC), fgFR4 is abundantly expressed and essential in controlling the carcinogenic action of FGF19 in liver cancer. Research shows that FGF19 when overexpressed, can connect to FGFR4 and set off a series of events that boost cell growth and stop death. Often linked to the activation of the GSK3β/β-catenin pathway, which is essential for tumor metastases and resistance to cell death, this FGF19-FGFR4 signaling also improves the epithelial-mesenchymal transition (EMT), a mechanism allowing cancer cells to acquire migratory and invasive traits, hence supporting tumor spread.

Figure 1 illustrates the FGF19-FGFR4 mediated signaling pathway, showing how FGF19 activates various signaling branches through its receptor FGFR4 and co-receptor β-Klotho, influencing key cellular functions in hepatocellular carcinoma (HCC) cells. Figure 1. FGF19-FGFR4 mediated signaling pathway. (Lu X, et al., 2018)

Moreover, FGFR4 overexpression in HCC cells has been linked to enhanced cell survival and chemoresistance. For instance, too high FGF19 expression has been found to downregulate reactive oxygen species (ROS) signaling, therefore shielding liver cancer cells from oxidative stress-induced death. This mechanism helps several chemotherapeutic drugs, including sorafenib, to be resisted, so FGFR4 is a crucial component in the evolution of drug resistance in HCC.

FGFR4 Targeting in Cancer Treatment

Targeting FGFR4 has become a viable therapeutic approach since this receptor is crucial in accelerating liver cancer development. Small compounds that particularly impede FGFR4 signaling or antibodies that target the receptor are among the several FGFR inhibitors in clinical investigation now. These treatments seek to upset the abnormal signaling in tumors therefore lowering cell count and improving the efficacy of chemotherapy.

To reduce off-target effects, recent research has further underlined the need to create selective FGFR4 inhibitors. Approved for use in many malignancies, multi-targeted RTK inhibitors such as anlotinib, lenvatinib, and regorafenib also block other kinases, which cause major side effects. With fewer side effects, more focused treatments emphasizing especially on FGFR4 could have a superior therapeutic index.

New approaches to specifically target FGFR4 for cancer treatment are being developed as our knowledge of the molecular mechanisms behind FGFR4 signaling gets more thorough. Small chemical inhibitors that particularly bind to the kinase domain of FGFR4 and hence prevent its activation and downstream signaling are one interesting direction. Furthermore under investigation as a possible therapy for tumors including liver, pancreatic, and colorectal cancers with high FGFR4 expression are monoclonal antibodies aimed against FGFR4.

Moreover, the creation of selective inhibitors aiming at just FGFR4 while sparing other members of the FGFR family might offer a more exact therapy approach. The most efficient inhibitors and their pharmacological characteristics for therapeutic application are yet unknown, hence researchers are researching these aspects.

References:

Levine KM, Ding K, et al. FGFR4: A promising therapeutic target for breast cancer and other solid tumors. Pharmacol Ther. 2020 Oct;214:107590.
Houthuijzen JM. For Better or Worse: FFAR1 and FFAR4 Signaling in Cancer and Diabetes. Mol Pharmacol. 2016 Dec;90(6):738-743.
Lu X, Chen H, Patterson AV, et al. Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects. J Med Chem. 2019 Mar 28;62(6):2905-2915.

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