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    • Unlike the LMW FGF isoform which is

    2018-10-20

    Unlike the LMW FGF2 isoform, which is well-studied, the HMW isoforms of FGF2 are not nearly as well-understood, but recent reports have investigated the effects of HMW FGF2 signaling in various contexts. Localization of FGF2 isoforms can vary depending on cellular conditions and stimuli (Arese et al., 1999). HMW isoforms have been described in some occasions to be present in the extracellular space, released through a process known as vesicle shedding (Greber et al., 2007; Taverna et al., 2003). The vesicles have the potential to stimulate plasminogen activator production and influence chemotaxis (Taverna et al., 2003), suggesting a role for HMW FGF2 in this process, and previous studies have shown that the 24kDa FGF2 isoform administered exogenously to endothelial myc inhibitor induces cell proliferation with a similar dose response to the 18kDa isoform (Taverna et al., 2003), suggesting a potential role for extracellular, canonical FGFR signaling by HMW FGF2 isoforms. In HEK293 cells, overexpression of HMW FGF2 led to chromatin compaction and apoptosis in a manner dependent on its localization to the nucleus, further supporting the important role of subcellular localization in the biology of HMW FGF2 (Ma et al., 2007). Mice specifically overexpressing HMW FGF2 isoforms quickly develop osteoarthropathy, associated with dysregulated expression of inflammatory proteins and cytokines (Meo Burt et al., 2016), and HMW FGF2 has also recently been implicated in cardiac fibrosis and cardiomyocyte hypertrophy in rats (Jiang et al., 2007; Santiago et al., 2014). Previously, it had been demonstrated that, in neonatal rat cardiac non-myocytes, hypertrophic stimuli result in upregulation and subsequent secretion of HMW FGF2 to the extracellular space (Santiago et al., 2011). Taken together, these reports suggest non-redundant functions of HMW FGF2 compared to LMW FGF2, as well as the potential of HMW FGF2 to be present and active not only intracellularly, but also in the extracellular milieu in certain scenarios. Human dermal fibroblasts express multiple isoforms of FGF2 as well as select FGF receptors (FGFRs) (Dailey et al., 2005; Dvorak et al., 2005; Eiselleova et al., 2009; Grose and Dickson, 2005; Quarto and Amalric, 1994; Root and Shipley, 2000). The LMW (18kDa) isoform of FGF2 has been studied most robustly and is reported to act in autocrine, intracrine, and paracrine manners, through interactions with its cell-surface receptors, the FGFRs (Ornitz et al., 1996; Zhang et al., 2006). Four distinct genes that encode for FGF receptors have been identified, FGFR1, FGFR2, FGFR3, and FGFR4 (Arese et al., 1999; Arnaud et al., 1999; Dvorak et al., 2005; Eiselleova et al., 2009; Florkiewicz and Sommer, 1989; Sperger et al., 2003; Taverna et al., 2003). Furthermore, alternative mRNA splicing produces several receptor variants, which exhibit varied binding kinetics and affinities for different FGF ligands (Champion-Arnaud et al., 1991; Miki et al., 1992; Root and Shipley, 2000). The variety of FGF ligands and FGFR variants provides a high level of diversity in ligand-binding specificity and biological function, depending on which FGFRs are expressed by various cell types and which FGFs are present in the surrounding milieu. Binding of the FGF2 ligand to its receptor triggers receptor dimerization, phosphorylation of its kinase domain, and signal transduction via activation of several intracellular pathways that have been implicated in multiple aspects of vertebrate and invertebrate embryonic development, tumor growth, angiogenesis, wound healing, and physiology (Ornitz and Marie, 2002; Powers et al., 2000; Spivak-Kroizman et al., 1994). Dysregulated expression of FGFs has also been implicated in cancer development and progression (Ezzat and Asa, 2005; Givol and Yayon, 1992; Krejci et al., 2012; Presta et al., 2005; Zubilewicz et al., 2001). Investigation of the ability of each FGF isoform to bind to different FGF receptors and activate downstream signaling pathways, and identification of FGF-FGFR pair specificities, is critical for understanding the biological mechanisms involved in normal development and pathogenesis. Previous studies have identified the 18kDa FGF2 as an important factor for the maintenance of pluripotency in human stem cells (Eiselleova et al., 2009; Zoumaro-Djayoon et al., 2011), and our lab has demonstrated that the 18kDa FGF2 isoform, in combination with sub-atmospheric oxygen, induces expression of stem cell specific genes and proteins in human dermal fibroblasts cultured in vitro (Page et al., 2009).