Dimerization of FGFR3 t(4;14) translocation mutants

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
~15% of multiple myelomas contain translocations that put the FGFR3 gene under the control of the strong IGH locus (Chesi, 1997; Avet-Loiseau, 1998). This translocation results in the overexpresssion of FGFR3 (Chesi, 1997), which leads to aberrant signaling in either a ligand-dependent (Otsuki, 1999; Qing, 2009) or independent fashion (Chesi, 2001). Overexpression of WT FGFR3 results in a low level of FGF-independent MAPK activation, suggesting that overexpression can lead to ligand-independent dimerization; however this response is more pronounced after ligand-stimulation (Chesi, 2001; Qing, 2009). ~5% of multiple myelomas with FGFR3 translocations also contain coding sequence activating mutations (Chesi, 1997; Avet-Loiseau, 1998). These mutations (R248C, Y373C, K650E and K650M) mimic activating mutations seen in bone development disoders, are believed to arise later in tumor progression than the translocation event and contribute to ligand-independent signaling (Chesi, 1997; Chesi, 2001; Li, 2001; Ronchetti, 2001).
Literature References
PubMed ID Title Journal Year
9207791 Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3

Kuehl, WM, Nardini, E, Chesi, M, Brents, LA, Schröck, E, Bergsagel, PL, Ried, T

Nat Genet 1997
10568829 Expression of fibroblast growth factor and FGF-receptor family genes in human myeloma cells, including lines possessing t(4;14)(q16.3;q32. 3) and FGFR3 translocation

Otsuki, T, Kurebayashi, J, Ueki, A, Sakaguchi, H, Taniwaki, M, Yamada, O, Yata, K, Nakazawa, N, Yawata, Y

Int J Oncol 1999
19381019 Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice

Stephan, JP, Dornan, D, Stinson, S, Wiesmann, C, Du, X, Wu, P, Qing, J, Ashkenazi, A, Wu, Y, Tien, J, French, D, Totpal, K, Chan, P, Chen, Y, Marsters, S, Ross, S, Li, H, Wang, QR, Stawicki, S

J Clin Invest 2009
11290605 The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells

Hawley, TS, Patterson, B, Chesi, M, Plowright, EE, Stewart, AK, Bergsagel, PL, Zhu, YX, Hawley, RG, Li, Z

Blood 2001
11429702 Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations

Otsuki, T, Lombardi, L, Colombo, G, Greco, A, Compasso, S, Neri, A, Ronchetti, D, Dell'Era, P

Oncogene 2001
9865713 High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies

Harousseau, JL, Talmant, P, Li, JY, Avet-Loiseau, H, Jaccard, A, Facon, T, Bataille, R, Rapp, MJ, Morineau, N, Trimoreau, F, Maloisel, F, Brigaudeau, C

Cancer Res 1998
11157491 Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma

Mesri, EA, Kuehl, WM, Ely, SA, Chesi, M, Brents, LA, Bergsagel, PL, Bais, C, Robbiani, DF

Blood 2001
Functional status

Gain of function of FGFR3 (4;14) translocation mutants [plasma membrane]

Disease Entity
Name Identifier Synonyms
multiple myeloma DOID:9538
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cite Us!