Mini review
Functions of Fibroblast Growth Factor Receptors in cancer defined by novel translocations and mutations

https://doi.org/10.1016/j.cytogfr.2015.03.003Get rights and content
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Abstract

The four receptor tyrosine kinases (RTKs) within the family of Fibroblast Growth Factor Receptors (FGFRs) are critical for normal development but also play an enormous role in oncogenesis. Mutations and/or abnormal expression often lead to constitutive dimerization and kinase activation of FGFRs, and represent the primary mechanism for aberrant signaling. Sequencing of human tumors has revealed a plethora of somatic mutations in FGFRs that are frequently identical to germline mutations in developmental syndromes, and has also identified novel FGFR fusion proteins arising from chromosomal rearrangements that contribute to malignancy. This review details approximately 200 specific point mutations in FGFRs and 40 different fusion proteins created by translocations involving FGFRs that have been identified in human cancer. This review discusses the effects of these genetic alterations on downstream signaling cascades, and the challenge of drug resistance in cancer treatment with antagonists of FGFRs.

Abbreviations

ARMS
alveolar rhabdomyosarcoma
BSS
Beare Stevenson cutis gyrata syndrome
CFS
chromosomal fragile site
CC
coiled coil domain
EMS
8p11 myeloproliferative syndrome (EMS)
ERMS
embryonal rhabdomyosarcoma
FN
fibronectin domain
Ig
immunoglobulin-like domain
IMD
IRSp53/MIM domain
ITD
internal tandem duplication
JM
juxtamembrane domain
LIsH
LIS1-homologous domain
LZ
leucine zipper domain
KD
kinase domain
KI
kinase insert domain
LADD
lacrimo auriculo dento digital syndrome
ORF
open reading frame
RMS
rhabdomyosarcoma
SAM
sterile alpha motif
SADDAN
severe achondroplasia with delayed development and acanthosis nigricans
SP
signal peptide
SPFH
stomatin/prohibitin/flotillin/HflK/C domain
TK domain
tyrosine kinase domain
TD
thanatophoric dysplasia
TM
transmembrane domain
ZF
zinc finger domain

Keywords

Fibroblast Growth Factor Receptor
Translocation
Development
Rhabdomyosarcoma
Myeloproliferative syndrome

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Leandro H. Gallo is a graduate student researcher in the Donoghue group in the Department of Chemistry & Biochemistry at the University of California, San Diego. He obtained his B.S. degree in Biological Sciences from Hunter College, City University of New York. He is currently in his fourth year of doctoral thesis studying the activation of IKKbeta, the regulatory kinase of the NFkappaB inflammatory signaling pathway, via a novel Lys63-linked ubiquitin modification.

Katelyn N. Nelson is a graduate student in the Donoghue group in the Department of Chemistry & Biochemistry at the University of California, San Diego. She earned her B.S. in Biochemistry at California State University, Long Beach. Her research focuses on identifying and characterizing novel oncogenic signaling mechanisms and interactions, specifically in the FGFR pathway.

April N. Meyer is a Staff Research Associate in Dr. Daniel J. Donoghue's laboratory at the University of California, San Diego. She earned her B.S. degree from the University of California, San Diego in the Department of Chemistry & Biochemistry. Her areas of expertise include cell biology and FGFR signaling.

Daniel J. Donoghue received his Ph.D. from MIT in 1979, after which he conducted postdoctoral research at the Salk Institute for Biological Studies. He has been on the faculty of UC San Diego since 1982. He has had a long-standing interest in Receptor Tyrosine Kinases (RTKs) and their roles in development and oncogenesis, especially the Fibroblast Growth Factor Receptors (FGFR). Currently, his lab exploits proteomic and genomic approaches to identify novel sites of posttranslational modifications, protein–protein interactions, and gene interaction networks.