N-Terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos-dependent phospholipid synthesis activation

Portal, Maximiliano M; Ferrero, G.; Caputto, Beatriz L.

doi:10.1038/sj.onc.1210137

Cited by 33 publications

(54 citation statements)

References 29 publications

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“…As a consequence of this interaction on the monolayers, c-Fos can modulate the activity of phospholipases at the interfacial level (18,45,46). To add complexity to the interpretation of this regulatory mechanism, the fact that tyrosine phosphorylation/dephosphorylation events on c-Fos influence its ER association (14) should also be considered as plausible for glycolipid synthesis activation. The finding that c-Fos increases GlcCerS V max values for both substrates without substantially modifying the K m values does not rule out either of these possibilities.…”

Section: Glccersmentioning

confidence: 99%

“…c-Fos/ER association/dissociation and consequently its capacity to activate phospholipid synthesis is regulated by the phosphorylation state of c-Fos tyrosine residues: quiescent cells contain small amounts of c-Fos, which is tyrosine-phosphorylated and dissociated from the ER membranes. Upon induction of cells to re-enter growth, concomitant with the induction of c-Fos expression, preexisting c-Fos is dephosphorylated, it associates to the ER, and it activates phospholipid synthesis (14).…”

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confidence: 99%

“…In PC12 cells induced to undergo differentiation by feeding of cells with nerve growth factor (NGF) (11), c-fos transcription is rapidly * This work was supported in part by grants from the Aqencia Nacional de induced (12,13), c-Fos associates to the ER and activates the synthesis of phospholipids necessary for membrane biogenesis associated to cell growth and neurite formation (10). Only ER-associated c-Fos is capable of activating phospholipid synthesis (14). c-Fos/ER association/dissociation and consequently its capacity to activate phospholipid synthesis is regulated by the phosphorylation state of c-Fos tyrosine residues: quiescent cells contain small amounts of c-Fos, which is tyrosine-phosphorylated and dissociated from the ER membranes.…”

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confidence: 99%

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c-Fos Activates Glucosylceramide Synthase and Glycolipid Synthesis in PC12 Cells

Crespo

Silvestre

Gil

et al. 2008

Journal of Biological Chemistry

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It has been demonstrated that c-Fos has, in addition to its well recognized AP-1 transcription factor activity, the capacity to associate to the endoplasmic reticulum and activate key enzymes involved in the synthesis of phospholipids required for membrane biogenesis during cell growth and neurite formation. Because membrane genesis requires the coordinated supply of all its integral membrane components, the question emerges as to whether c-Fos also activates the synthesis of glycolipids, another ubiquitous membrane component. We show that c-Fos activates the metabolic labeling of glycolipids in differentiating PC12 cells. Specifically, c-Fos activates the enzyme glucosylceramide synthase (GlcCerS), the product of which, GlcCer, is the first glycosylated intermediate in the pathway of synthesis of glycolipids. By contrast, the activities of GlcCer galactosyltransferase 1 and lactosylceramide sialyltransferase 1 are essentially unaffected by c-Fos. Co-immunoprecipitation experiments in cells co-transfected with c-Fos and a V5-tagged version of GlcCerS evidenced that both proteins participate in a physical association. c-Fos expression is tightly regulated by specific environmental cues. This strict regulation assures that lipid metabolism activation will occur as a response to cell requirements thus pointing to c-Fos as an important regulator of key membrane metabolisms in membrane biogenesis-demanding processes.Membrane biogenesis is a complex process that couples nuclear responses to growing environmental cues with appropriate morphological and functional changes of the cell. The proteins and lipids that are required for cell membrane expansion, i.e. during cell proliferation, neuritogenesis, tumorigenesis, etc. are provided by a complex endomembrane system whose major constituents are the endoplasmic reticulum (ER) 5 and the Golgi complex. Phospholipids, together with cholesterol and integral membrane proteins, are synthesized in the ER and incorporated into preexisting membrane. Nascent membranes bud at ER exit sites and move by vesicular transport toward the plasma membrane passing through the Golgi complex where a series of post-translational modifications on cargo and membrane-bound proteins occur. The lipid composition of membranes is also adjusted in the Golgi complex by the addition of glycolipids and sphingomyelin. Finally, at the most trans region of the Golgi, vesicles are targeted to their final destination: the plasma membrane, endosomes, lysosomes, among others.Although the molecular and cellular basis of intracellular vesicle transport has been described in detail (reviewed in Ref. 1), less is known about the molecular mechanisms that enable the endomembrane system to adapt to fluctuations in the cell's demands of the membrane according to its diverse functional states. It can be anticipated that, in cells that are actively involved in proliferation or in plasma membrane extension processes that demand massive membrane biogenesis, the organellar homeostasis must be different to that of cells that...

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Section: Glccersmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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c-Fos Activates Glucosylceramide Synthase and Glycolipid Synthesis in PC12 Cells

Crespo

Silvestre

Gil

et al. 2008

Journal of Biological Chemistry

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“…c-Fos-ER association and consequently the capacity of c-Fos to activate phospholipid synthesis, is regulated by the phosphorylation state of tyrosine (tyr) residues #10 and #30 of c-Fos: quiescent cells contain small amounts of c-Fos, which is tyr-phosphorylated and is neither associated to the ER membranes nor does it activate phospholipid synthesis. However, on induction of cells to re-enter growth, c-Fos expression rapidly increases, c-Fos is dephosphorylated and is found associated to the ER membranes and capable of activating phospholipid synthesis (Portal et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The small amount of c-Fos present in quiescent cells is tyrphosphorylated, is dissociated from the ER membranes and does not activate phospholipid synthesis. However, on induction of the cell to re-enter growth, c-Fos expression is rapidly induced, it is found dephosphorylated, associated to ER membranes and activating phospholipid synthesis (Portal et al, 2007). Herein, using in vivo and in vitro experimental strategies, we show that the kinase c-Src is capable of phosphorylating tyr residues of c-Fos whereas the phosphatase TC45 T-cell protein-tyr phosphatase (TC-PTP) dephosphorylates them, thus enabling c-Fos/ER association and activation of phospholipid synthesis.…”

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confidence: 99%

The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity

2011

Self Cite

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Our previous work showed that in T98G cells, a human glioblastoma multiforme-derived cell line, the association of c-Fos to the endoplasmic reticulum (ER) and consequently, the capacity of c-Fos to activate phospholipid synthesis, is regulated by the phosphorylation state of tyrosine (tyr) residues #10 and #30 of c-Fos. The small amount of c-Fos present in quiescent cells is tyrphosphorylated, is dissociated from the ER membranes and does not activate phospholipid synthesis. However, on induction of the cell to re-enter growth, c-Fos expression is rapidly induced, it is found dephosphorylated, associated to ER membranes and activating phospholipid synthesis (Portal et al., 2007). Herein, using in vivo and in vitro experimental strategies, we show that the kinase c-Src is capable of phosphorylating tyr residues of c-Fos whereas the phosphatase TC45 T-cell protein-tyr phosphatase (TC-PTP) dephosphorylates them, thus enabling c-Fos/ER association and activation of phospholipid synthesis. Results also suggest that the regulation of the phosphorylation/dephosphorylation cycle of c-Fos occurs at the TC-PTP level: induction of cells to re-enter growth promotes the translocation of TC45 from a nuclear to a cytoplasmic location concomitant with its activation. Activated TC45 in its turn promotes dephosphorylation of pre-formed c-Fos, enabling cells to rapidly activate phospholipid synthesis to respond to its growth demands.

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Mechanistic insights into the nongenomic regulation of phospholipid synthesizing enzymes

Gizzi

Caputto

2013

IUBMB Life

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Lipid synthesis is a complex process regulated at multiple levels. Here, we will discuss nongenomic regulatory mechanisms, particularly the activation and/or recruitment of key enzymes to membranes. The phospholipid synthesis enzymes Lipin and CTP:phosphocholine cytidylyltransferase are taken as examples of these mechanisms that are mediated by posttranslational modifications or by an intrinsic property of the enzyme that senses lipid composition. In addition, special emphasis will be put on another relevant non genomic lipid synthesis regulation mechanism that is dependent on c-Fos, a protein that has deserved less attention so far. This latter regulatory mechanism is emerging as an important determinant for processes that require high rates of lipid synthesis such as those of growth and proliferation. V C 2013 IUBMB Life, 65(7): [584][585][586][587][588][589][590][591][592] 2013

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N-Terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos-dependent phospholipid synthesis activation

Cited by 33 publications

References 29 publications

c-Fos Activates Glucosylceramide Synthase and Glycolipid Synthesis in PC12 Cells

c-Fos Activates Glucosylceramide Synthase and Glycolipid Synthesis in PC12 Cells

The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity

Mechanistic insights into the nongenomic regulation of phospholipid synthesizing enzymes

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