Mitotic Phosphorylation of Cdc25B Ser321 Disrupts 14-3-3 Binding to the High Affinity Ser323 Site

Astuti, Puji; Boutros, Rose; Ducommun, Bernard; Gabrielli, Brian

doi:10.1074/jbc.m110.138412

Cited by 25 publications

(29 citation statements)

References 33 publications

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“…PKA-and PKGImediated phosphorylation of S7 of Rap1GAP2 triggered the removal of 14-3-3 from its binding site at phosphorylated S9, whereas thrombin and ADP treatment enhanced the phosphorylation of S9 and the association of Rap1GAP2 and 14-3-3. 18 Another example of the inhibition of 14-3-3 binding by the phosphorylation of the Ϫ2 serine relative to the actual 14-3-3-binding site has been described for Cdc25B 35 and Cdc25C 36 involving CdkI and Cdc2 kinases. 35,36 To understand the consequences of 14-3-3 binding for RGS18 function, we investigated downstream signaling events.…”

Section: Discussionmentioning

confidence: 99%

“…18 Another example of the inhibition of 14-3-3 binding by the phosphorylation of the Ϫ2 serine relative to the actual 14-3-3-binding site has been described for Cdc25B 35 and Cdc25C 36 involving CdkI and Cdc2 kinases. 35,36 To understand the consequences of 14-3-3 binding for RGS18 function, we investigated downstream signaling events. In initial studies, we verified the interaction of RGS18 with Gq and Gi (data not shown) and confirmed that RGS18 blocks the Gq-mediated release of Ca 2ϩ from intracellular stores.…”

Section: Discussionmentioning

confidence: 99%

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Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets

Gegenbauer

Elia

Blanco

et al. 2012

Blood

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Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein for the G-␣-q and G-␣-i subunits of heterotrimeric Gproteins that turns off signaling by G-protein coupled receptors. RGS18 is highly expressed in platelets. In the present study, we show that the 14-3-3␥ protein binds to phosphorylated serines 49 and 218 of RGS18. Platelet activation by thrombin, thromboxane A2, or ADP stimulates the association of 14-3-3 and RGS18, probably by increasing the phosphorylation of serine 49. In contrast, treatment of platelets with prostacyclin and nitric oxide, which trigger inhibitory cyclic nucleotide signaling involving cyclic AMP-dependent protein kinase A (PKA) and cyclic GMP-dependent protein kinase I (PKGI), induces the phosphorylation of serine 216 of RGS18 and the detachment of 14-3-3. Serine 216 phosphorylation is able to block 14-3-3 binding to RGS18 even in the presence of thrombin, thromboxane A2, or ADP. 14-3-3-deficient RGS18 is more active compared with 14-3-3-bound RGS18, leading to a more pronounced inhibition of thrombin-induced release of calcium ions from intracellular stores. Therefore, PKA-and PKGI-mediated detachment of 14-3-3 activates RGS18 to block Gq-dependent calcium signaling. These findings indicate cross-talk between platelet activation and inhibition pathways at the level of RGS18 and Gq. IntroductionIn healthy vasculature, endothelial cells lining the blood vessels constantly produce and release prostacyclin (PGI 2 ) and nitric oxide (NO) into the vessel lumen. The interaction of endothelial factors with platelets plays a fundamental role in controlling hemostasis and in maintaining platelets in a resting state. Platelet inhibition by both PGI 2 and NO has been well established. The signaling pathways of both molecules result in an elevation of cyclic nucleotides that activate cyclic AMP-dependent protein kinase A (PKA) and cyclic GMP-dependent protein kinase I (PKGI). These in turn phosphorylate an unknown number of substrate proteins, resulting in reduced release of calcium ions (Ca 2ϩ ) from intracellular stores and reduced activation of G-proteins such as Rap1, ultimately leading to a block of platelet adhesion, granule release, and aggregation. PKA and PKGI have overlapping substrate specificities, which may explain the synergistic role of the 2 pathways. Few substrates have been established in platelets, among them Rap1GAP2, a GTPase-activating protein (GAP) of the small G-protein Rap1, as we have shown previously. 1 Other substrates include vasodilator-stimulated phospho-protein (VASP), heatshock protein 27 (HSP27), and LIM and SH3 domain protein (LASP), all of which regulate actin dynamics. 2,3 The IP 3 -receptor and the IP 3 -receptor-associated G-kinase substrate (IRAG) are the only PKA and/or PKGI substrates that have been shown to mediate cAMP/cGMP effects on intracellular Ca 2ϩ release. [2][3][4] Limited data are available on the specific substrates and signaling events that translate PKA/G substrate phosphorylation into platelet inhibition.Conversely, bindin...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets

Gegenbauer

Elia

Blanco

et al. 2012

Blood

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“…[246] Expression of the phosphorylation-mimicking Cdc25B1 S321D prevents p38 mediated phosphorylation of S323 and abolishes binding by 14-3-3β and 14-3-3ε. [246,259] 14-3-3σ binding is unaffected by S321 phosphorylation. [259] 14-3-3σ preferentially interacts with Cdc25B3 S230 [216] and is induced by p53 following activation by ATM/Chk2.…”

Section: Cdk1 Phosphorylation Of Cdc25 Precludes Checkpoint Mediated mentioning

confidence: 97%

“…[246,259] 14-3-3σ binding is unaffected by S321 phosphorylation. [259] 14-3-3σ preferentially interacts with Cdc25B3 S230 [216] and is induced by p53 following activation by ATM/Chk2. [260] Figure 4.…”

Section: Cdk1 Phosphorylation Of Cdc25 Precludes Checkpoint Mediated mentioning

confidence: 97%

“…S99, S148, S178, S192, S204, S206, T226, S234, S359, T561, S567, T569 [60,156,157,162] Cdk1-cyclin B S18, S40, S88, S116, S261, S283, S321 [149,151,167] Chk1 S76, S124, S178, T507 [168][169][170][171][172][173]200] Chk2 S124, S278 [173,175] Casein Kinase 1ε S82 [199] Casein Kinase 1α S79, S82 [198] p38 S76, S124 [168,175] GSK-3β S76 [193,194] NEK11 S82, S88 [187] Plk3 S80 [193,194] Cdk1-cyclinB S50, S160, S321 [135,136,246] Chk1 S151, S230, S323, S563 [236,238,239] Aurora S353 [124] Casein Kinase 2 S186, S187 [235] JNK S101, S103 [280] MEK/ERK S249 [259] p38 S323 [208] MK2 S323 [210] Plk1 T167, S209, T404, S465 [136] Cdk1/cyclin B T48, T67, S122, T130, S168, S214 [42,143,145,246] Chk1 S216, S247, S263 [219-221, 225, 226] Chk2 S216 [209,242] Casein Kinase 2 T236 …”

Section: Speciesmentioning

confidence: 99%

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Phosphorylation Mediated Regulation of Cdc25 Activity, Localization and Stability

Frazer¹,

Young²

2012

Protein Phosphorylation in Human Health

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Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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Entry into mitosis is triggered by the activation of cyclin‐dependent kinase 1 (Cdk1). This simple reaction rapidly and irreversibly sets the cell up for division. Even though the core step in triggering mitosis is so simple, the regulation of this cellular switch is highly complex, involving a large number of interconnected signalling cascades. We do have a detailed knowledge of most of the components of this network, but only a poor understanding of how they work together to create a precise and robust system that ensures that mitosis is triggered at the right time and in an orderly fashion. In this review, we will give an overview of the literature that describes the Cdk1 activation network and then address questions relating to the systems biology of this switch. How is the timing of the trigger controlled? How is mitosis insulated from interphase? What determines the sequence of events, following the initial trigger of Cdk1 activation? Which elements ensure robustness in the timing and execution of the switch? How has this system been adapted to the high levels of replication stress in cancer cells?

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Mitotic Phosphorylation of Cdc25B Ser321 Disrupts 14-3-3 Binding to the High Affinity Ser323 Site

Cited by 25 publications

References 33 publications

Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets

Regulator of G-protein signaling 18 integrates activating and inhibitory signaling in platelets

Phosphorylation Mediated Regulation of Cdc25 Activity, Localization and Stability

Triggering mitosis

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