Fgfr3, fibroblast growth factor receptor 3, is a transmembrane kinase protein. It is expressed in chondrocytes and mature osteoblasts, regulating bone growth. Its signaling is involved in multiple pathways, and it plays a vital role in embryogenesis and is relevant in tumorigenesis [3,4,5]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

Mutations in Fgfr3 cause achondroplasia, the most common form of dwarfism in humans, along with related chondrodysplasia syndromes. The gain-of-function mutations lead to increased signaling through mechanisms like receptor stabilization, enhanced dimerization, and tyrosine kinase activity, which paradoxically suppress growth plate chondrocyte proliferation and maturation, reducing bone elongation [3,4]. In 3-4% of human glioblastomas, the FGFR3-TACC3 fusion occurs, constitutively activating FGFR3 kinase signaling and promoting cell proliferation and tumor progression [1]. In bladder cancer, FGFR3 mutations are present in up to half of cases, influencing tumorigenesis, the tumor microenvironment, and responses to immune checkpoint inhibitors. FGFR inhibitors like Erdafitinib show initially promising but transient efficacy, and understanding resistance mechanisms is crucial [2]. In colorectal cancer, FGFR3 overexpression is a frequent alteration, associated with an unfavorable prognosis in metastases and potentially a therapeutic target [5]. In ovarian cancer, FGFR3 overexpression enhances cisplatin-resistance by promoting EGFR phosphorylation and activating the PI3K/AKT pathway [6].

In conclusion, Fgfr3 is essential for bone growth regulation. Studies using mouse models have revealed its role in skeletal development and its implications in various diseases such as dwarfism-related syndromes, glioblastoma, bladder, colorectal, and ovarian cancers. Understanding Fgfr3's functions through these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Gött, Hanna, Uhl, Eberhard. 2022. FGFR3-TACCs3 Fusions and Their Clinical Relevance in Human Glioblastoma. In International journal of molecular sciences, 23, . doi:10.3390/ijms23158675. https://pubmed.ncbi.nlm.nih.gov/35955806/

2. Noeraparast, Maxim, Krajina, Katarina, Pichler, Renate, Ahyai, Sascha, Pichler, Martin. 2024. FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies. In Cancer communications (London, England), 44, 1189-1208. doi:10.1002/cac2.12602. https://pubmed.ncbi.nlm.nih.gov/39161208/

3. Ornitz, David M, Legeai-Mallet, Laurence. 2017. Achondroplasia: Development, pathogenesis, and therapy. In Developmental dynamics : an official publication of the American Association of Anatomists, 246, 291-309. doi:10.1002/dvdy.24479. https://pubmed.ncbi.nlm.nih.gov/27987249/

4. Horton, William A, Hall, Judith G, Hecht, Jacqueline T. . Achondroplasia. In Lancet (London, England), 370, 162-172. doi:10.1016/S0140-6736(07)61090-3. https://pubmed.ncbi.nlm.nih.gov/17630040/

5. Fromme, J E, Schildhaus, H-U. . [FGFR3 overexpression is a relevant alteration in colorectal cancer]. In Der Pathologe, 39, 189-192. doi:10.1007/s00292-018-0504-0. https://pubmed.ncbi.nlm.nih.gov/30267148/

6. Zhao, Jing, Tan, Wenxi, Zhang, Lingyi, Cui, Manhua, Zhao, Shuhua. 2021. FGFR3 phosphorylates EGFR to promote cisplatin-resistance in ovarian cancer. In Biochemical pharmacology, 190, 114536. doi:10.1016/j.bcp.2021.114536. https://pubmed.ncbi.nlm.nih.gov/33794187/