Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1

Blagoveshchenskaya, Anastasia; Cheong, Fei Ying; Rohde, Holger M.; Glover, Greta; Knödler, Andreas; Nicolson, Teresa; Boehmelt, Guido; Mayinger, Peter

doi:10.1083/jcb.200708109

Cited by 138 publications

(239 citation statements)

References 35 publications

(54 reference statements)

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“…That is, under conditions of growth factor limitation, hSac1 is localized to Golgi membranes, whereas it redistributes to the ER upon growth factor resupply (Blagoveshchenskaya et al, 2008). These data are consistent with hSac1 inhibiting membrane trafficking in cells experiencing growth factor distress, and hSac1 relocalization to the ER as release of the trafficking brake upon growth factor supplementation (Blagoveshchenskaya et al, 2008). Yet, in yeast (Rivas et al, 1999) and now in mammals, it is essential that Sac1 PIP phosphatase activity be localized to ER membranes for proper biological function.…”

Section: A Role For Sac1 In Regulating Nuclear Pip Signaling?supporting

confidence: 77%

The Sac1 Phosphoinositide Phosphatase Regulates Golgi Membrane Morphology and Mitotic Spindle Organization in Mammals

Liu

Boukhelifa

Tribble

et al. 2008

MBoC

131

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Phosphoinositides (PIPs) are ubiquitous regulators of signal transduction events in eukaryotic cells. PIPs are degraded by various enzymes, including PIP phosphatases. The integral membrane Sac1 phosphatases represent a major class of such enzymes. The central role of lipid phosphatases in regulating PIP homeostasis notwithstanding, the biological functions of Sac1-phosphatases remain poorly characterized. Herein, we demonstrate that functional ablation of the single murine Sac1 results in preimplantation lethality in the mouse and that Sac1 insufficiencies result in disorganization of mammalian Golgi membranes and mitotic defects characterized by multiple mechanically active spindles. Complementation experiments demonstrate mutant mammalian Sac1 proteins individually defective in either phosphoinositide phosphatase activity, or in recycling of the enzyme from the Golgi system back to the endoplasmic reticulum, are nonfunctional proteins in vivo. The data indicate Sac1 executes an essential household function in mammals that involves organization of both Golgi membranes and mitotic spindles and that both enzymatic activity and endoplasmic reticulum localization are important Sac1 functional properties. INTRODUCTIONSpatial and temporal regulation of intracellular signaling in eukaryotic cells involves the compartmentalization of membrane surfaces into discrete, albeit often transient, functional units. There are several biochemical strategies by which cells generate such units or domains. One well-established strategy uses the chemical diversity offered by phosphoinositides (PIPs), i.e., phosphorylated forms of phosphatidylinositol (PtdIns) (Majerus, 1997;Fruman et al., 1998;Strahl and Thorner, 2007). The chemical heterogeneity of individual PIP species permits the construction of chemically unique platforms on membrane surfaces that, in turn, recruit unique cohorts of proteins that drive specific biological reactions. Spatial and temporal control of such reactions requires a finely coordinated balance between the activities of the lipid kinases that produce PIPs and the activities of enzymes that degrade them. PIP turnover is catalyzed by two general classes of enzymes: phospholipases and PIP phosphatases.Although experimental scrutiny of the phospholipases has historically been more intense, recent demonstrations of the significant biological functions played by PTEN, the myotubularins, and synaptojanins highlight the general importance of PIP phosphatases (Wishart et al., 2001;Wishart and Dixon, 2002;Wenk and De Camilli, 2004).The SAC domain derives from the yeast Sac1 protein (ySac1; Cleves et al., 1989), and it represents a signature for PIP phosphatase catalytic activity . PIP phosphatases such as phosphatase and tensin homolog (mutated in multiple advanced cancers 1) (PTEN) (Maehama et al., 2001), synaptojanins (Cremona et al., 1999), and synaptojanin-like proteins (Srinivasan et al., 1997;Stolz et al., 1998) all harbor SAC domains. The prototypical member of this family, ySac1, catalyzes the dephosphoryla...

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Section: A Role For Sac1 In Regulating Nuclear Pip Signaling?supporting

confidence: 77%

The Sac1 Phosphoinositide Phosphatase Regulates Golgi Membrane Morphology and Mitotic Spindle Organization in Mammals

Liu

Boukhelifa

Tribble

et al. 2008

MBoC

131

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“…During serum deprivation, Sac1 has been reported to traffic from the ER to the Golgi (6) and to down-regulate PI(4)P levels there. Recent studies have proposed that ER Sac1 also regulates PI(4)P at the PM (6,36). To test whether endogenous mammalian ER Sac1 is capable of regulating PI(4)P in our system, we recruited ER membranes tagged with CFP-CB5-FKBP into apposition with the Golgi using the Golgi anchor Tgn38-FRB and rapamycininduced dimerization (Table 1).…”

Section: Pmmentioning

confidence: 99%

“…In addition, transient apposition between organelles can alter phosphoinositide levels by presenting membrane-bound phosphatases in trans. For example, the endoplasmic reticulum (ER) can make contacts with the Golgi, allowing 4-phosphatases of the ER to dephosphorylate Golgi phosphatidylinositol 4-phosphate [PI(4)P] (6)(7)(8).…”

mentioning

confidence: 99%

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current

Dickson

Jensen

Hille

2014

Proc. Natl. Acad. Sci. U.S.A.

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Plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] regulates the activity of many ion channels and other membrane-associated proteins. To determine precursor sources of the PM PI(4,5)P 2 pool in tsA-201 cells, we monitored KCNQ2/3 channel currents and translocation of PH PLCδ1 domains as real-time indicators of PM PI(4,5)P 2 , and translocation of PH OSH2×2 , and PH OSH1 domains as indicators of PM and Golgi phosphatidylinositol 4-phosphate [PI(4)P], respectively. We selectively depleted PI(4)P pools at the PM, Golgi, or both using the rapamycin-recruitable lipid 4-phosphatases. Depleting PI(4)P at the PM with a recruitable 4-phosphatase (Sac1) results in a decrease of PI(4,5)P 2 measured by electrical or optical indicators. Depleting PI(4)P at the Golgi with the 4-phosphatase or disrupting membrane-transporting motors induces a decline in PM PI(4,5)P 2 . Depleting PI(4)P simultaneously at both the Golgi and the PM induces a larger decrease of PI(4,5)P 2 . The decline of PI(4,5)P 2 following 4-phosphatase recruitment takes 1-2 min. Recruiting the endoplasmic reticulum (ER) toward the Golgi membranes mimics the effects of depleting PI(4)P at the Golgi, apparently due to the trans actions of endogenous ER Sac1. Thus, maintenance of the PM pool of PI(4,5)P 2 appears to depend on precursor pools of PI(4)P both in the PM and in the Golgi. The decrease in PM PI(4,5)P 2 when Sac1 is recruited to the Golgi suggests that the Golgi contribution is ongoing and that PI (4,5)P 2 production may be coupled to important cell biological processes such as membrane trafficking or lipid transfer activity.phosphoinositides | wortmannin | pleckstrin homology domain T his paper concerns the dynamics of cellular pools of phosphoinositides, a family of phospholipids located on the cytoplasmic leaflet of cellular membranes, that maintain cell structure, cell motility, membrane identity, and membrane trafficking; they also play key roles in signal transduction (1). Phosphatidylinositol (PI) can be phosphorylated at three positions to generate seven additional species. The subcellular localization of each phosphoinositide is tightly governed by the concurrent presence of lipid kinases and lipid phosphatases (2, 3), giving each membrane within the cell a unique and dynamic phosphoinositide signature (4). Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] is localized to the inner leaflet of the plasma membrane (PM) and is the major substrate of phospholipase C (PLC). As a consequence, PI(4,5)P 2 levels are dynamically regulated by G q -coupled receptors activating PLC. The activity of lipid kinases and phosphatases also can be modulated by signaling; for example, a PI 4-kinase, when associated with neuronal calcium sensor-1, is accelerated in response to elevated calcium that occurs with PI(4,5)P 2 cleavage (5). In addition, transient apposition between organelles can alter phosphoinositide levels by presenting membrane-bound phosphatases in trans. For example, the endoplasmic reticulum (ER) can make contacts with the...

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“…The retrieval of mammalian SAC1 from the Golgi to the ER in the presence of growth factors or mitogens is controlled by COPI-mediated retrograde transport and requires the p38 MAPK pathway (23). Although the regulation of SAC1 retrieval from the Golgi has been reported, little is known about the control of SAC1 export from the ER under conditions of serum starvation.…”

Section: Significancementioning

confidence: 99%

“…It has been reported previously that SAC1 is localized to the Golgi membranes only when cells are starved for nutrients or growth factors, but remains in the ER under normal growth conditions (23,24). Given the role for PI(4)P in vesicle traffic from the trans Golgi network, starvation conditions that lodge SAC1 and thus deplete the local supply of PI(4)P in the Golgi may suppress anterograde traffic in cells that must cease net cell growth.…”

Section: Significancementioning

confidence: 99%

Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum

Pahuja

Wang

Blagoveshchenskaya

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Most secretory cargo proteins in eukaryotes are synthesized in the endoplasmic reticulum and actively exported in membrane-bound vesicles that are formed by the cytosolic coat protein complex II (COPII). COPII proteins are assisted by a variety of cargo-specific adaptor proteins required for the concentration and export of secretory proteins from the endoplasmic reticulum (ER). Adaptor proteins are key regulators of cargo export, and defects in their function may result in disease phenotypes in mammals. Here we report the role of 14-3-3 proteins as a cytosolic adaptor in mediating SAC1 transport in COPII-coated vesicles. Sac1 is a phosphatidyl inositol-4 phosphate (PI4P) lipid phosphatase that undergoes serum dependent translocation between the endoplasmic reticulum and Golgi complex and controls cellular PI4P lipid levels. We developed a cell-free COPII vesicle budding reaction to examine SAC1 exit from the ER that requires COPII and at least one additional cytosolic factor, the 14-3-3 protein. Recombinant 14-3-3 protein stimulates the packaging of SAC1 into COPII vesicles and the sorting subunit of COPII, Sec24, interacts with 14-3-3. We identified a minimal sorting motif of SAC1 that is important for 14-3-3 binding and which controls SAC1 export from the ER. This LS motif is part of a 7-aa stretch, RLSNTSP, which is similar to the consensus 14-3-3 binding sequence. Homology models, based on the SAC1 structure from yeast, predict this region to be in the exposed exterior of the protein. Our data suggest a model in which the 14-3-3 protein mediates SAC1 traffic from the ER through direct interaction with a sorting signal and COPII.

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Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1

Cited by 138 publications

References 35 publications

The Sac1 Phosphoinositide Phosphatase Regulates Golgi Membrane Morphology and Mitotic Spindle Organization in Mammals

The Sac1 Phosphoinositide Phosphatase Regulates Golgi Membrane Morphology and Mitotic Spindle Organization in Mammals

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current

Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum

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Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1

Cited by 138 publications

References 35 publications

The Sac1 Phosphoinositide Phosphatase Regulates Golgi Membrane Morphology and Mitotic Spindle Organization in Mammals

The Sac1 Phosphoinositide Phosphatase Regulates Golgi Membrane Morphology and Mitotic Spindle Organization in Mammals

Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P 2 and maintenance of KCNQ2/3 ion channel current

Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum

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Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P ₂ and maintenance of KCNQ2/3 ion channel current