Download SCIENTIFIC ACHIEVEMENTS My laboratory was the first to identify

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).