FGFR2

Official Full Name

fibroblast growth factor receptor 2

Organism

Homo sapiens

GeneID

2263

Background

The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative 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 of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]

Synonyms

BEK; JWS; BBDS; CEK3; CFD1; ECT1; KGFR; TK14; TK25; BFR-1; CD332; K-SAM;

Bio Chemical Class

Kinase

Protein Sequence

MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPGREKEITASPDYLEIAIYCIGVFLIACMVVTVILCRMKNTTKKPDFSSQPAVHKLTKRIPLRRQVTVSAESSSSMNSNTPLVRITTRLSSTADTPMLAGVSEYELPEDPKWEFPRDKLTLGKPLGEGCFGQVVMAEAVGIDKDKPKEAVTVAVKMLKDDATEKDLSDLVSEMEMMKMIGKHKNIINLLGACTQDGPLYVIVEYASKGNLREYLRARRPPGMEYSYDINRVPEEQMTFKDLVSCTYQLARGMEYLASQKCIHRDLAARNVLVTENNVMKIADFGLARDINNIDYYKKTTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLMWEIFTLGGSPYPGIPVEELFKLLKEGHRMDKPANCTNELYMMMRDCWHAVPSQRPTFKQLVEDLDRILTLTTNEEYLDLSQPLEQYSPSYPDTRSSCSSGDDSVFSPDPMPYEPCLPQYPHINGSVKT

Open

Disease

Alzheimer disease, Bladder cancer, Breast cancer, Hepatitis virus infection, Liver cancer, Myeloproliferative neoplasm, Oral mucositis, Periodontal disease, Retina cancer, Solid tumour/cancer, Stomach cancer

Approved Drug

3 +

Clinical Trial Drug

9 +

Discontinued Drug

1 +

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Detailed Information

FGFR2 gene, located on human chromosome 10q26, is a transmembrane protein with functions such as development regulating, and FGFR2 belongs to tyrosine kinase receptor. The structure of FGFR2 is mainly composed of three parts: extracellular region, transmembrane region and intracellular region. The extracellular region is a massive glycosylated ligand binding region consisting of three typical immunoglobulin (Ig) -like domains and acid regions between three domains, including Ig i, Ig ii, and Ig iii. Ig iii of FGFR2 is encoded by three exons, whose mRNA can be spliced alternately, making the C-terminal of Ig iii as a highly variable region. The diversity and specificity of ligand binding is determined by Ig iii of FGFR2. The transmembrane portion with a helical structure may be missing so as to form secretory FGFR2 and possess the ability to bind to FGFs. It is noted that FGFR2 transmembrane only happens once. The intracellular portion consists mainly of a domain with tyrosine kinase activity (TK1 and TK2). FGFR2, as a member of FGFRs, has three characteristics: (1) overlapping recognition and multi-specificity, that is, FGFR2 can bind to several FGFs with similar affinity; (2) FGFR2 binding to its ligand depends on cell surface heparin sulfate proteoglycan; (3) The same gene can produce many cytobinding and secretory FGFR2 receptors.

FGFR2 associated with Cholangiocarcinoma

Cholangiocarcinoma is an invasive tumor that originates from the bile duct. Unfortunately, most patients have advanced disease, so the survival rate is less than 2%. FGFR is abnormally activated in about 15% -20% of intrahepatic cholangiocarcinoma. FGFR has become an effective treatment strategy, which can benefit 70%-80% of patients with intrahepatic cholangiocarcinoma. Krook et al. have confirmed their hypothesis by using cell lines that can stably express these FGFR2 mutants to study the drug sensitivity in vitro. Through proteomic methods, they found that PI3K/Akt/ mTOR signaling pathway upregulated in cells expressing FGFR2p.e565a. In addition, they further tested the effect of mTOR inhibitors and confirmed that these cells were sensitive to FGFR2 inhibition. In conclusion, understanding how the secondary mutation of FGFR2 influences the sensitivity to different FGFR inhibitors and the development of reasonable combination therapy are very important to improve the clinical outcome of FGFR patients.

FGFR2 associated with breast cancer

FGFR2 is a member of the receptor tyrosine kinase subfamily, which also includes FGFR1, FGFR3, and FGFR4. There is increasing evidence that the FGF-FGFR2 signaling pathway plays an important role in breast cancer. Gene amplification and overexpression of FGFR2 in breast cancer tissues have also been described, especially in triple-negative breast cancer. Therefore, FGFR2 overexpression and inhibitor studies have been carried out using human cell models to support FGFR2's tumor-promoting function in breast cancer. The impact of crosstalk between FGFR2 and ER on the formation of tamoxifen resistance was studied by Sadej's group. They found that activation of the FGF7/FGFR2 axis could eliminate the growth inhibition of tamoxifen in cells exposed to medium with CAFs. It was also found that the activation of the PI3K/Akt pathway which targeted ER-Ser167 and the regulation of Bcl-2 expression after FGF7 treatment was the basis of FGFR2 to depend on tamoxifen resistance. Analysis of tissue samples with invasive ductal breast cancer revealed that the expression of FGFR2 was negatively correlated with the expression of ER. Their study has first demonstrated that the signaling pathways based on FGF7/ FGFR2 can regulate the function of the endoplasmic reticulum and influence the response between breast cancer cells and tamoxifen.

FGFR2 Figure 1. FGFR2 paracrine signaling (Li et al., 2020).

References:

Li F, Peiris M N, Donoghue D J. Functions of FGFR2 corrupted by translocations in intrahepatic cholangiocarcinoma[J]. Cytokine & growth factor reviews, 2020, 52: 56-67.
Krook M A, Lenyo A, Wilberding M, et al. Efficacy of FGFR inhibitors and combination therapies for acquired resistance in FGFR2-fusion cholangiocarcinoma[J]. Molecular cancer therapeutics, 2020, 19(3): 847-857.
Turczyk L, Kitowska K, Mieszkowska M, et al. FGFR2-driven signaling counteracts tamoxifen effect on ERα-positive breast cancer cells[J]. Neoplasia, 2017, 19(10): 791-804.

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