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SCIENTIFIC ACHIEVEMENTS My laboratory was the first to identify and characterize the enzyme responsible for PtdIns(3,5)P2 and PtdIns5P intracellular production in mammalian cells, which we called PIKfyve, a name used ever since (Shisheva et al., MCB, 1999; Sbrissa et al., JBC, 1999; Sbrissa et al., JBC 2002). The discovery for the first time that selective perturbation of PtdIns(3,5)P2 production by PIKfyve results in endomembrane dilation, formation of multiple cytoplasmic vacuoles and a major defect in fluid phase endocytosis, whereas that of PtdIns5P affects actin stress fiber remodeling (Ikonomov et al., JBC, 2001; Ikonomov et al., JBC 2002, Ikonomov et al., MBC, 2003, Sbrissa et al., Endocrinology, 2004; Sbrissa et al., AJP-Cell, 2012). We have provided to the community the first valuable means for functional dissociation between PIKfyve-synthesized PtdIns5P and PtdIns(3,5)P2 (Sbrissa et al., AJP-Cell, 2012). Using in vitro reconstitution assays of endosome fusion and fission, we demonstrated for the first time that PIKfyve negatively regulates endosome fusion but positively affects endosome fission. Thus, agents, perturbing PIKfyve activity triggered endosome fusion inhibiting endosome fission, and vice versa, activating interactions to increase PIKfyve activity accelerated endosome fission (Ikonomov et al., AJP-Cell, 2006; Sbrissa et al., JBC, 2007). The creation of the first mouse model with systemic ablation of PIKfyve and the discovery that the lack of PIKfyve causes embryonic death as early as the preimplantation stage (Ikonomov et al., JBC, 2011). We were the first to identify that PIKfyve-catalyzed production of PtdIns(3,5)P2 and PtdIns5P requires a regulatory protein, ArPIKfyve (gene symbol VAC14), that was cloned and characterized in my laboratory for the first time (Sbrissa et al., MCB, 2004). The phosphatase Sac3 (gene symbol FIG4), responsible for dephosphorylation of PtdIns(3,5)P2 has been identified and characterized for the first time in my laboratory (Sbrissa et al., JBC, 2007). My laboratory has elucidated for the first time that the three proteins, i.e., PIKfyve, ArPIKfyve and Sac3, form a common ternary complex, the PAS complex, that is necessary and sufficient for regulating PtdIns(3,5)P2 synthesis and turnover (Sbrissa et al., JBC, 2007; Sbrissa et al., JMB, 2008). We were the first to identify the molecular mechanism of the Charcot Marie Tooth 4J neuropathy, caused by a compound heterozygous null and point Sac3 (FIG4)I41T mutation. This mechanism involves unusually fast degradation of Sac3I41T, because, contrary to Sac3WT, mutant Sac3I41T is unable to be protected by ArPIKfyve from proteasome degradation (Ikonomov et al., JBC 2010). We have provided the groundbreaking evidence that PIKfyve is a positive regulator of insulin sensitivity both in vivo and in the cell context. We generated the first mouse model with PIKfyve conditional ablation in muscle tissue (MPIfKO) and demonstrated that the MPIfKO mice have severe insulin resistance and other characteristic features of prediabetes (Ikonomov et al, AJP-Endocrinol & Metabol, 2013). The above and other achievements by our laboratory have been recently reviewed by us (Shisheva, Curr Top Microbiol & Immunol, 2012; Shisheva, ABB, 2013, Ikonomov, Sbrissa & Shisheva, Bioessays, 2015) and others (Ho et al., Traffic, 2012).