A Tissue-Specific Atlas of Mouse Protein Phosphorylation and Expression

Huttlin, Edward L.; Jedrychowski, Mark P.; Elias, Joshua E.; Goswami, Tapasree; Rad, Ramin; Beausoleil, Sean A.; Villén, Judit; Haas, Wilhelm; Sowa, Mathew E.; Gygi, Steven P.

doi:10.1016/j.cell.2010.12.001

Cited by 1,630 publications

(1,895 citation statements)

References 64 publications

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“…Given the relatively high expression levels of RALDHs in the brain (4,30), it is likely that the enzymatic activity of RALDHs is acutely regulated by posttranslational modifications, such as phosphorylation. Indeed, phosphorylation sites on RALDHs have been reported by recent quantitative phosphoproteomics studies (32)(33)(34)(35)(36)(37)(38). Further work is needed to elucidate how CaN may directly or indirectly modulate RALDH activity in neurons through regulation of various phosphorylation sites.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Arendt

Zhang

Ganesan

et al. 2015

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

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Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

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Section: Discussionmentioning

confidence: 99%

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Arendt

Zhang

Ganesan

et al. 2015

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

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“…From these data we conclude that reciprocal phosphorylation/ O-GlcNAcylation interplay does not occur on sites targeted by Pro-directed kinases. This finding is of tremendous importance, since Pro-directed kinases represent in frequency about 40% of all human phosphorylation sites (28,29).…”

Section: Reciprocal Interplay Does Not Occur On Ser/thr Sites Targetementioning

confidence: 99%

Elucidating crosstalk mechanisms between phosphorylation and O-GlcNAcylation

Leney

Atmioui

et al. 2017

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

138

127

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Proteins can be modified by multiple posttranslational modifications (PTMs), creating a PTM code that controls the function of proteins in space and time. Unraveling this complex PTM code is one of the great challenges in molecular biology. Here, using mass spectrometry-based assays, we focus on the most common PTMs-phosphorylation and O-GlcNAcylation-and investigate how they affect each other. We demonstrate two generic crosstalk mechanisms. First, we define a frequently occurring, very specific and stringent phosphorylation/ O-GlcNAcylation interplay motif, (pSp/T)P(V/A/T)(gS/gT), whereby phosphorylation strongly inhibits O-GlcNAcylation. Strikingly, this stringent motif is substantially enriched in the human (phospho)proteome, allowing us to predict hundreds of putative O-GlcNAc transferase (OGT) substrates. A set of these we investigate further and show them to be decent substrates of OGT, exhibiting a negative feedback loop when phosphorylated at the P-3 site. Second, we demonstrate that reciprocal crosstalk does not occur at PX(S/T)P sites, i.e., at sites phosphorylated by proline-directed kinases, which represent 40% of all sites in the vertebrate phosphoproteomes.O-GlcNAcylation | phosphorylation | crosstalk | signaling | regulation

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“…52 The following instrument parameters were employed: fully tryptic or LysC digestion, up to 2 missed cleavages, precursor mass tolerance of §25 ppm, 1.0 Da product ion mass tolerance, a static modification of carbamidomethylation on cysteine (C57.0214); and dynamic modifications for phosphorylation on serine, threonine, and tyrosine (C79.9663), methionine oxidation (C15.9949), and 13 C 6 15 N 2 -lysine (C8.0142). Spectra were searches using SEQUEST and matched to peptides with a 1% FDR using the target decoy approach 53 and subsequently analyzed using linear discriminant analysis to derive Xcorr, DCn 0 , precursor mass error, and charge state. The Ascore method 54,55 was used to assign phosphorylation sites and peptides quantified as described previously.…”

Section: Mass Spectrometrymentioning

confidence: 99%

Phosphorylation of Atg9 regulates movement to the phagophore assembly site and the rate of autophagosome formation

Feng¹,

Backues²,

Baba³

et al. 2016

Autophagy

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Macroautophagy is primarily a degradative process that cells use to break down their own components to recycle macromolecules and provide energy under stress conditions, and defects in macroautophagy lead to a wide range of diseases. Atg9, conserved from yeast to mammals, is the only identified transmembrane protein in the yeast core macroautophagy machinery required for formation of the sequestering compartment termed the autophagosome. This protein undergoes dynamic movement between the phagophore assembly site (PAS), where the autophagosome precursor is nucleated, and peripheral sites that may provide donor membrane for expansion of the phagophore. Atg9 is a phosphoprotein that is regulated by the Atg1 kinase. We used stable isotope labeling by amino acids in cell culture (SILAC) to identify phosphorylation sites on this protein and identified an Atg1-independent phosphorylation site at serine 122. A nonphosphorylatable Atg9 mutant showed decreased autophagy activity, whereas the phosphomimetic mutant enhanced activity. Electron microscopy analysis suggests that the different levels of autophagy activity reflect differences in autophagosome formation, correlating with the delivery of Atg9 to the PAS. Finally, this phosphorylation regulates Atg9 interaction with Atg23 and Atg27.

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A Tissue-Specific Atlas of Mouse Protein Phosphorylation and Expression

Cited by 1,630 publications

References 64 publications

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Elucidating crosstalk mechanisms between phosphorylation and O-GlcNAcylation

Phosphorylation of Atg9 regulates movement to the phagophore assembly site and the rate of autophagosome formation

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