The presence of FBP in nuclei
The presence of FBP2 in nuclei seems to accompany the cells' potential to divide as it has been shown that during differentiation of the satellite cells (myogenic progenitor cells) the amount of nuclear FBP2 decreases and in differentiated myotubes, the localisation of FBP2 is restricted to cytoplasm (Gizak et al., 2006). This observation is in agreement with studies on subcellular distribution of FBP2 in cardiomyocytes and cancer cells which have demonstrated that FBP2 accumulates in nuclei of cardiomyocytes (HL-1 cell line) and lung cancer cells (KLN205 cells and samples of primary human squamous lung cancer) during S and G2 stage of the Levodopa synthesis (Mamczur et al., 2012). Interestingly, the block of the cell cycle progression by withdrawal of serum from a culture medium which results in a quiescent, G0-like cell stage not only stimulates FBP2 export from nuclei to cytoplasm but also significantly reduces the amount of the enzyme simultaneously elevating the level of mRNA for FBP2 (Mamczur et al., 2012). In HL-1 cardiomyocytes, nuclear transport of FBP2 is stimulated by norepinephrine acting through β1 receptors (Gizak et al., 2009). Activation of β1-adrenergic receptor (β1-AR) in cardiomyocytes is known to activate cAMP-dependent protein kinase (PKA) regulating several important steps in the process of cellular growth and differentiation of cardiac myocytes (Zou et al., 1999). It has been shown that activation of the β1-AR signalling accelerates the rate of HL-1 proliferation while its disruption increases mortality of HL-1 cells (Gizak et al., 2009). Except activation of PKA, cAMP can also stimulate phosphoinositide 3-kinase (PI3K), and inhibition of PI3K results in FBP2 withdrawal from the nuclei of HL-1 cells (Gizak et al., 2009). Thus, the signalling cascades activated by PKA and PI3K can jointly contribute to the cAMP-regulated cell survival (Fig. 5). GSK3 is another protein kinase which affect nuclear accumulation of FBP2. Inhibition of this kinase, apart from influencing FBP2-ALDOA and FBP2-mitochondria interactions, also reduces the amount of nuclear FBP2 (Gizak et al., 2012a). The physiological meaning of this finding is unclear because although GSK3 may promote proliferation it can also act as a tumour suppressor, depending on GSK3 isoform and cell types (McCubrey et al., 2014; Beurel et al., 2015; Ruvolo, 2017; Ruzzene et al., 2017). The fact that GSK3 is inhibited by the PI3K signalling (for review see e.g. Hermida et al., 2017) adds another complication to this picture. A precise nuclear action of FBP2 is poorly understood. It has been shown that FBP2 can interact with several histone and non-histone nuclear proteins (Mamczur et al., 2012). Among FBP2 binding partners are proteins participating in formation of interchromatin granule clusters, the structures involved in mRNA processing (Saitoh et al., 2004). Several of them, e.g., Myb-binding protein 1A, RNPs and helicases, are known to operate in a cell cycle-dependent manner. Thus, it cannot be excluded that FBPase participates in cell cycle-dependent mRNA processing (Mamczur et al., 2012). On the other hand, FBP2 can interact with components of the Myb-binding protein 1A/nucleolin/nucleophosmin complex (MNN complex). Since the MNN complex negatively regulates the G1/S transition by associating with several transcription factors (e.g. c-Myb and NF-kappaB) (Yamauchi et al., 2008) thus, it was hypothesised that nuclear FBP2 regulates the cell cycle by modulating the liberation of some of the transcription factors from the MNN complex (Mamczur et al., 2012). Because the Myb family proteins also contribute directly to the G2/M transition (Nakata et al., 2007) the ability of FBP2 to associate with MNN may explain nuclear localisation of the enzyme during the S and G2 stages. While the mechanism of nuclear import of FBP2 relies on well-defined and studied canonical motif KKKGK (Gizak et al., 2009), the mechanism of FBP2 export from nuclei for a long time has been enigmatic. The hydrophobic motif LGEFVL (190–195), a hypothetical candidate for nuclear export sequence (NES), is located in interface of upper and lower dimer and is inaccessible to export machinery. The recent findings of Wisniewski et al. (Wiśniewski et al., 2017) demonstrating that FBP2 may function as a mixture of dimers and tetramers has thrown light on this conundrum. It has turned out that a recombinant form FBP2 with the L190G substitution, which is not able to adopt tetrameric conformation, localises solely in cytoplasm. However, the block of nuclear export with Leptomycin B traps FBP2 dimeric mutant in nuclei (Wiśniewski et al., 2017).