A motif-based profile scanning approach for genome-wide prediction of signaling pathways

Yaffe, Michael B.; Leparc, Germán; Lai, Jack H.; Obata, Toshiyuki; Volinia, Stefano; Cantley, Lewis C.

doi:10.1038/86737

Cited by 496 publications

(416 citation statements)

References 29 publications

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“…The results indicated that Cdc25A also play a role in meiotic resumption of mouse oocytes. The differences in GVBD-inducing ability of the two phosphatases, Cdc25A and Cdc25B, suggest that they have different substrates and nonredundant functions (Solc et al, 2008 (Yaffe et al, 2001;Obenauer et al, 2003). This program has been quite successful and some predictions have been experimentally verified (Gratton et al, 2001;Zhou et al, 2001;Gottlieb et al, 2002;Kim et al, 2002Kim et al, , 2005She et al, 2004;Park et al, 2006;Lemeer et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase a modulates Cdc25B activity during meiotic resumption of mouse oocytes

Zhang

et al. 2008

Developmental Dynamics

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Protein kinase A (PKA) play a critical role in maintaining the meiotic arrest. However, the steps downstream of PKA remain largely unknown. In this study, we investigated the regulation of meiotic resumption by PKA/Cdc25B pathway in mouse oocytes. Injection of mRNA coding for Cdc25b-S321A had a more potent maturation-inducing ability than Cdc25b-WT. When co-injected with PKA inhibitor, Cdc25B-WT had similar activities with Cdc25B-S321A. Meanwhile, the phosphorylation of Cdc25B-S321 was detected in germinal vesicle (GV) oocytes by Western blotting with a phospho-Ser321-specific antibody and the band disappeared when oocytes reenter into the meiotic cell cycle. Furthermore, Cdc25B-WT translocated to the nucleus shortly before GV breakdown (GVBD), whereas phosphorylated Cdc25B-S321 expressed exclusively in the cytoplasm and the signal could not be detected in GVBD oocytes. Taken together, these data indicate that Cdc25B-Serine321 is the potential PKA target and Cdc25B subcellular localization determines its function during the process of maintaining GV arrest in mouse oocytes. Developmental Dynamics 237: 3777-3786, 2008.

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Section: Introductionmentioning

confidence: 99%

Protein kinase a modulates Cdc25B activity during meiotic resumption of mouse oocytes

Zhang

et al. 2008

Developmental Dynamics

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“…To assess which BI 4834-sensitive phosphorylation sites might be generated by PLK1 we made use of the Scansite algorithm. This algorithm identifies amino acid sequences matching kinase consensus motifs based on in vitro kinase assays on oriented peptide libraries (28,39). In addition to the initial set of 28 kinase motifs (28) currently available in Scansite, the mitotic kinases PLK1, Aurora kinase A and B, as well as NEK2 were also recently characterized and included in Scansite (29).…”

Section: Bioinformatic Analysis Of Bi 4834-regulated Phosphorylationmentioning

confidence: 99%

Quantitative Phospho-proteomics to Investigate the Polo-like Kinase 1-Dependent Phospho-proteome

Grosstessner-Hain

Hegemann

Novatchkova

et al. 2011

Molecular & Cellular Proteomics

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Polo-like kinase 1 (PLK1) is a key regulator of mitotic progression and cell division, and small molecule inhibitors of PLK1 are undergoing clinical trials to evaluate their utility in cancer therapy. Despite this importance, current knowledge about the identity of PLK1 substrates is limited. Here we present the results of a proteome-wide analysis of PLK1-regulated phosphorylation sites in mitotic human cells. We compared phosphorylation sites in HeLa cells that were or were not treated with the PLK1-inhibitor BI 4834, by labeling peptides via methyl esterification, fractionation of peptides by strong cation exchange chromatography, and phosphopeptide enrichment via immobilized metal affinity chromatography. Analysis by quantitative mass spectrometry identified 4070 unique mitotic phosphorylation sites on 2069 proteins. Of these, 401 proteins contained one or multiple phosphorylation sites whose abundance was decreased by PLK1 inhibition. These include proteins implicated in PLK1-regulated processes such as DNA damage, mitotic spindle formation, spindle assembly checkpoint signaling, and chromosome segregation, but also numerous proteins that were not suspected to be regulated by

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“…M, I, L, V, F, W or C) [48]. The requirement for R residues at position n-3 is very stringent, whereas R at n-5 appears not to be so stringent [46][47][48]. The sequence 170 LNRLLT 175 located in the PX domain of PLD2 thus conforms a putative consensus site for AKT kinase phosphorylation.…”

Section: Discussionmentioning

confidence: 96%

“…This antibody recognizes peptides and proteins containing phospho-(S/T) preceded by R at position n-3 and/or n-5 [RXRXX(pS/pT)], the suggested consensus site for AKT kinase phosphorylation (Fig. 3A) [46][47][48]. As shown in Figure 3B, the AKT substrate antibody detected a band corresponding to immunoprecipitated mycPLD2 WT (~106 kDa), suggesting that PLD2 WT is phosphorylated in S/T within a consensus site for AKT kinase phosphorylation.…”

Section: Pld2 As a Putative Akt Substratementioning

confidence: 99%

Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner

Fulvio

Frondorf

Gómez‐Cambronero

2008

Cellular Signalling

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Phospholipase D2 (PLD2), one of the two mammalian members of the PLD family, has been implicated in cell proliferation, transformation, tumor progression and survival. However, as precise mechanistic details are still unknown, we investigated here if the PLD2 isoform would signal through the PI3K/AKT pathway. Transient expression of PLD2 in COS7 cells with either the WT or with a Y179F mutant, resulted in an increased basal phosphorylation of AKT in residues T 308 and S 473 , in a PI3K-dependent manner. Transfection of PLD2-Y179F (but not the wild type) caused an increased (>2-fold) DNA synthesis even in the absence of extracellular stimuli. Other signaling mechanisms downstream such PLD/PI3K dependence (that might lead to DNA synthesis regulation), were further studied. PLD2-Y179F caused an increase in phosphorylation of p42/p44 ERK and in the expression of G 0 /G 1 phase transition markers, p21 CIP and PCNA, and these effects, too, were dependent on PI3K. Interestingly, Akt once activated, enabled the phosphorylation of PLD2 on residue T 175 , an effect that was inhibited by LY296004. Lastly, if PLD2-Y179F is further mutated in residue K758 (PLD2 Y179F-K758R), which renders inactive a catalytic site, DNA synthesis is then abrogated, indicating that the activity of the enzyme (i.e. synthesis of PA) is necessary for the observed effects.In conclusion, the unavailability of residue Y179 on PLD2 to become phosphorylated leads to an augmentation of DNA synthesis concomitantly with MEK and AKT phosphorylation, in a process that is dependent on PI3K and independent of any extracellular stimuli. This might be critical for the maintenance of the PLD2-regulated proliferative status.

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A motif-based profile scanning approach for genome-wide prediction of signaling pathways

Cited by 496 publications

References 29 publications

Protein kinase a modulates Cdc25B activity during meiotic resumption of mouse oocytes

Protein kinase a modulates Cdc25B activity during meiotic resumption of mouse oocytes

Quantitative Phospho-proteomics to Investigate the Polo-like Kinase 1-Dependent Phospho-proteome

Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner

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