Basic fibroblast growth factor (FGF‐2): The high molecular weight forms come of age

Abstract

After over thirty years from its discovery, research on basic fibroblast growth factor (FGF-2) keeps revealing new aspects of the complexity of its gene expression as it evolved in the eukaryotic organisms. The discovery of multiple forms of FGF-2 generated by alternative translation from AUG and non-canonical CUG codons on the same mRNA transcript has led to the characterization of a low molecular weight (LMW) FGF-2 form and various high molecular weight (HMW) forms (four in humans). In this review, we discuss the biochemical features and biological activities of the different FGF-2 forms. In particular, we focus on the properties that are unique to the HMW forms and its biological functions.

Endogenously produced FGF2 is essential for the survival and proliferation of cultured mouse spermatogonial stem cells

“…The single-copy FGF2 gene generates one low-molecular weight (LMW) and several high-molecular weight (HMW) protein isoforms as a result of alternative translation initiations. While the HMW isoforms predominantly localize to the nucleus and signal independently of FGFR, the LMW isoform (also known as sFGF2) is predominantly found in the cytoplasm and released from the cells to execute its function through binding to membrane FGF receptors (FGFR1-4), activating the kinase activity of FGFRs and downstream signaling molecules such as PI3K-AKT, RAS-RAF-MAPK [3]. In the present study, using cultured mouse spermatogonia (mSPG) that possess stem cell activity, we investigated the role, the source, the mechanism, and the target genes of FGF2 in the IVP and stem cell activity of cultured mSPG.…”

Biomarkers of PARP inhibitor sensitivity

“…There is in vitro evidence, of varying strength, to support as potentially biomarkers of PARP inhibitor sensitivity, BRCA1/2 sporadic mutation [8], BRCA1 promoter methylation [9,10], BRCA1 suppression in the absence of methylation [10], PTEN deficient cancers [11], ATM mutation [12,13], MRE11 dominant negative mutations in mismatch repair deficient cancers [14], and FANCF promoter methylation [15]. This list can likely be simplified in that each tumour type differs in the potential mechanism of HR deficiency, and therefore each tumour type may ultimately be defined by a panel of biomarkers.…”

Thrombin cleaves the high molecular weight forms of basic fibroblast growth factor (FGF-2): a novel mechanism for the control of FGF-2 and thrombin activity

“…Translation of the 22, 22.5 and 24 kDa forms, known as high molecular weight (HMW) FGF-2, is initiated from CUG codons upstream of the AUG (Florkiewicz and Sommer, 1989;Prats et al, 1989;Vagner et al, 1995). The HMW forms of FGF-2 are therefore colinear extensions of 18 kDa FGF-2 (Sorensen et al, 2006;Yu et al, 2007). Post-translational methylation of arginine residues in the RG-rich N-terminal end controls nuclear accumulation of HMW FGF-2 (Burgess et al, 1991;Pintucci et al, 1996;Klein et al, 2000).…”

“…All FGF-2 forms lack a conventional signal peptide sequence for secretion. However, all of them are released from cells following lethal or sublethal damage (Yu et al, 2007) or by other mechanisms (Mignatti et al, 1991;Piotrowicz et al, 1997;Taverna et al, 2003). HMW and LMW FGF-2 induces expression of different genes, thus generating unique phenotypes (Quarto et al, 2005).…”

“…The relative amount of FGF-2 forms differs among cell types and developmental stages (Yu et al, 2007). Furthermore, selective expression of HMW FGF-2 is induced by stress conditions such as heat shock and oxidative stress, cytokines and growth factors (Yu et al, 2007).…”