Functional studies of the mammalian Sac1 phosphoinositide phosphatase.
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abstract
The Sac1 PIP phosphatase is an enigmatic enzyme in that it occupies an intracellular location (ER) that is not normally associated with PIP signaling. Yet, genetic experiments in mice and silencing experiments in cultured cells report an essential housekeeping function for this protein. Detailed cellular analyses report maintenance of proper organization of the Golgi system, and of the mitotic spindle apparatus, are compromised when Sac1 functional thresholds are breached. While the Golgi derangements do not obviously affect protein transport through the organelle, the mitotic defects result in defects in progression through the G2/M stage of the cell cycle. Finally, both the catalytic PIP phosphatase activity, and its ability to be recycled back to the ER, represent essential functional features of the Sac1 enzyme. We expect that current insights for Sac1 will set the blueprint for future analyses of its functions. Many questions remain to be answered in this field: does Sac1 have important roles in ER and plasma membranes connections since ySac1 only degrades the plasma membrane-localized PtdIns 4-OH kinase Stt4 generated PtdIns-4-P? Does the ER-localized Sac1 play critical roles in regulating nuclear PIP signaling since ER is continuous with the nuclear envelope, and does it specifically happen in a certain stage during cell cycle progression? Does anchoring the Sac1-catalytic domain to other cellular membranes affect its function and what effects will be generated by mislocalizing the Sac1-catalytic domain to exotic membrane locations? Does the Golgi dispersion phenotype herald a crosstalk of the organelle with the mitotic apparatus (i.e. does Golgi disorganization provide ectopic nucleation sites for the -tubulin ring complex)? Clearly, there is much to be learned regarding the biological functions of Sac1-like lipid phosphatases, and we anticipate the discoveries yet to come will rival those derived from studies of the kinases - both in impact and in scope. 2009 Elsevier Ltd. All rights reserved.
