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    • Pleuromutilin In conclusion these data in

    2022-01-10

    In conclusion, these data in combination with previously described reports of GC-B being inactivated by dephosphorylation in response to other signaling molecules, strongly suggests that distinct hormonal systems inactivate GC-B by a general dephosphorylation mechanism. Identification of the modified GC-B phosphorylation sites will be an important next step in defining the molecular basis for how hormones and growth factors inhibit GC-B. RCS cells overexpressing GC-B are a promising system for addressing this issue, since physiological responsiveness to FGF is retained under conditions where GC-B protein levels are elevated about ten-fold over endogenous levels. Also, identifying the specific downstream signaling pathways required for the FGF2 inhibition of GC-B will be important to understand how FGF2 inhibits GC-B. Additionally, it will be interesting to determine whether long bone growth and/or long bone composition is changed in GC-B7E/7E compared to GC-BWT/WT mice or whether mice expressing dephosphorylated forms of GC-B are dwarfed. Finally, we suggest that understanding the cross-talk between the FGFR3 and GC-B signaling cascades is of increasing medical importance because a protease resistant analog of CNP is in clinical trials as a therapy for increasing longitudinal growth in children with dwarfism [48], [49]. However, a recent report showing higher circulating levels of CNP in children with achondroplasia suggests tissue resistance to CNP [50], which may result from increased dephosphorylation and desensitization of GC-B. In either instance, understanding the contribution of GC-B dephosphorylation and desensitization to achondroplasia is necessary to ensure drugs that specifically target GC-B will be effective therapeutics for achondroplasia.
    Conflict of interest
    Introduction Guanosine 3′,5′-cyclic monophosphate (cGMP) is important signaling molecule which controls a different physiological responses and processes in numerous prokaryotes and all eukaryotes. It is well known that in mammals cGMP plays important role in fundamental processes such as rot vision and regulation of Pleuromutilin (Lucas et al., 2000). In prokaryotes the role and signaling pathway of cGMP has only been explored in a few organisms, because of low level of this molecule. The involvement of cGMP was confirmed in formation of cyst in nitrogen fixing bacterium Rhodospirillum centeneum (Marden et al., 2011). Moreover, the guanylyl cyclase Cya2 from cyanobacteria Synechocystis PCC 6803 acts as osmosensor (Ochoa De Alda et al., 2000, Rauch et al., 2008). The number of reports confirming the role of cyclic GMP in plant cells is continuously growing. This signaling molecule is involved in stomatal opening and closing regulation (Dubovskaya et al., 2011, Cousson, 2001), seed germination (Teng et al., 2010), photoperiodic flower induction (Szmidt-Jaworska et al., 2004) and plant reactions to abiotic and biotic stress conditions (Meier et al., 2009Maathuis and Sander, 2001). A concentration of cyclic GMP is regulated by guanylyl cyclases (GCs) that catalyse the formation of cGMP from GTP and phosphodiesterases (PDEs) that hydrolyze cGMP to a non-cyclic 5′-guanosine monophosphate (GMP). The identification of GCs in higher plants is complicated by the fact that BLAST searches with annotated GCs from either higher or lower eukaryotes fail to identify any matches. This suggest that higher plants have evolved unique GC molecules where only the catalytic centre may show any degree of conservation (Ludidi and Gehring, 2003). Recent studies of plant guanylyl cyclases are focused on identification and functional analysis of a new family of membrane proteins called “moonlighting kinases with GC activity” with guanylyl cyclase catalytic center encapsulated within intracellular kinase domain (Irving et al., 2012). The structure of these proteins is completely different from animal counterparts where both domains are separated by linker sequence (Biswas et al., 2009). The new group of plant GCs included several receptor kinases such as brassinosteroid receptor (BRI1), phytosulfokine receptor 1 (PSKR1), pathogen peptide 1 receptor (PEPR1) and a wall associated receptor kinase 10 (WAKL10). Bioinformatic analysis revealed that all of these proteins and over 40 receptor-like kinases from Arabidopsis include highly conserved fourteen amino acid long catalytic motif. This motif serves as a foundation for the search for new plant GCs using bioinformatic tools (Wong et al., 2015).