Serine 727 Phosphorylation and Activation of Cytosolic Phospholipase A2 by MNK1-related Protein Kinases

Hefner, Ying; Börsch-Haubold, Angelika; Murakami, Makomoto; Wilde, Jonathan I.; Pasquet, Sophie; Schieltz, David; Ghomashchi, Farideh; Yates, John R.; Armstrong, Christopher G.; Paterson, Andrew J.; Cohen, Philip; Fukunaga, Rikiro; Hunter, Tony; Kudo, Ichiro; Watson, Steve P.; Gelb, Michael H.

doi:10.1074/jbc.m003395200

Cited by 213 publications

(196 citation statements)

References 41 publications

(87 reference statements)

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“…In the recent years, other substrates of MNKs have been identified such as heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), sprouty (SPRY2), cytoplasmic phospholipase A2 (cPLA2) and polypyrimidine-tract-binding proteinassociated splicing factor (PSF) (Hefner et al, 2000;Buxade et al, 2005;DaSilva et al, 2006;Guil et al, 2006;Buxade et al, 2008). Most of these substrates have been implicated in inflammatory response enhancing the production of pro-inflammatory cytokines such as tumor necrosis factor-a or eicosanoids (Hefner et al, 2000;Buxade et al, 2005). More work is required to identify other downstream targets of MNKs, and to understand the unique roles of MNK1 and MNK2 in mediating tumor growth and drug resistance.…”

Section: Discussionmentioning

confidence: 99%

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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Trastuzumab (Herceptin) resistance is a major obstacle in the treatment of patients with HER2-positive breast cancers. We recently reported that the transcription factor Y-box binding protein-1 (YB-1) leads to acquisition of resistance to trastuzumab in a phosphorylationdependent manner that relies on p90 ribosomal S6 kinase (RSK). To explore how this may occur we compared YB-1 target genes between trastuzumab-sensitive cells (BT474) and those with acquired resistance (HR5 and HR6) using genome-wide chromatin immunoprecipitation sequencing (ChIP-sequencing), which identified 1391 genes uniquely bound by YB-1 in the resistant cell lines. We then examined differences in protein expression and phosphorylation between these cell lines using the Kinexus Kinex antibody microarrays. Cross-referencing these two data sets identified the mitogen-activated protein kinase-interacting kinase (MNK) family as potentially being involved in acquired resistance downstream from YB-1. MNK1 and MNK2 were subsequently shown to be overexpressed in the resistant cell lines; however, only the former was a YB-1 target based on ChIP-PCR and small interfering RNA (siRNA) studies. Importantly, loss of MNK1 expression using siRNA enhanced sensitivity to trastuzumab. Further, MNK1 overexpression was sufficient to confer resistance to trastuzumab in cells that were previously sensitive. We then developed a de novo model of acquired resistance by exposing BT474 cells to trastuzumab for 60 days (BT474LT). Similar to the HR5/HR6 cells, the BT474LT cells had elevated MNK1 levels and were dependent on it for survival. In addition, we demonstrated that RSK phosphorylated MNK1, and that this phosphorylation was required for ability of MNK1 to mediate resistance to trastuzumab. Furthermore, inhibition of RSK with the small molecule BI-D1870 repressed the MNK1-mediated trastuzumab resistance. In conclusion, this unbiased integrated approach identified MNK1 as a player in mediating trastuzumab resistance as a consequence of YB-1 activation, and demonstrated RSK inhibition as a means to overcome recalcitrance to trastuzumab.

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Section: Discussionmentioning

confidence: 99%

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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“…The role of phosphorylation in membrane association of cPLA 2 -α is unclear but is has been demonstrated that phosphorylation events can, at least partially, contribute to cPLA 2 -α activation [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

Forsell

Olsson

Andersson

et al. 2005

Biochemical Pharmacology

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Polychlorinated biphenyls (PCBs) are stable compounds commonly found in nature as environmental pollutants. PCBs can affect the endocrine function of hormones such as steroid-hormones. Also, PCBs are known to be inducers of arachidonic acid release in various cells. We report, here, the effects of PCBs on eicosanoid formation, arachidonic acid release and cytosolic phospholipase A 2 -α(cPLA 2 -α) activation in human platelets. Ortho-substituted PCBs induced a time and dosedependent release of arachidonic acid and the concomitant formation of 12(S)-hydroxy-5,8-cis-10-trans-14-cis-eicosatetraenoic acid (12-HETE) and 12(S)-hydroxy-5-cis-8,10-transheptadecatrienoic acid (12-HHT) in human platelets. The release of arachidonic acid and the formation of 12-HETE was completely blocked by the cPLA 2 -α inhibitors AACOCF 3 or pyrrolidine-1. PCB-treatment of platelets demonstrated that the cPLA 2 -α protein as well as PLA 2 activity translocated to the membrane fraction, independent of a rise in intracellular Ca 2+ . Furthermore, electrophoretic gel mobility shift analysis of cPLA 2 -α on SDS-PAGE demonstrated a PCB-dependent phosphorylation of cPLA 2 -α. The effects of 17β-estradiol and two structurally unrelated anti-estrogens, nafoxidin and tamoxifen on PCB-induced arachidonic acid release in platelets were also investigated. Both nafoxidin and tamoxifen inhibited PCB-induced arachidonic acid release as well as 12-HETE and 12-HHT formation. Interestingly, platelets incubated with PCBs did not aggregate despite the fact that robust release of arachidonic acid was observed. In summary, these results demonstrate that certain PCBs induce activation of cPLA 2 -α independent of a rise in intracellular calcium and a robust release of arachidonic acid release with resulting eicosanoid formation in human platelets.

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“…Protein phosphatase 2A (PP2A) was from Calbiochem. PRAK and MSK1 were expressed, purified and activated as described in Hefner et al (2000); both are available from Upstate.…”

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confidence: 99%

Regulation of tyrosine hydroxylase by stress‐activated protein kinases

Toska

Kleppe

Armstrong

et al. 2002

Journal of Neurochemistry

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110

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Recombinant human tyrosine hydroxylase (hTH1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (MSK1) at Ser40 and by p38 regulated/activated kinase (PRAK) on Ser19. Phosphorylation by MSK1 induced an increase in V max and a decrease in K m for 6-(R)-5,6,7,8-tetrahydrobiopterin (BH 4 ), while these kinetic parameters were unaffected as a result of phosphorylation by PRAK. Phosphorylation of both Ser40 and Ser19 induced a high-affinity binding of 14-3-3 proteins, but only the interaction of 14-3-3 with Ser19 increased the hTH1 activity. The 14-3-3 proteins also inhibited the rate of dephosphorylation of Ser19 and Ser40 by 82 and 36%, respectively. The phosphorylation of hTH1 on Ser19 caused a threefold increase in the rate of phosphorylation of Ser40. These studies provide new insights into the possible roles of stress-activated protein kinases in the regulation of catecholamine biosynthesis.

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Serine 727 Phosphorylation and Activation of Cytosolic Phospholipase A2 by MNK1-related Protein Kinases

Cited by 213 publications

References 41 publications

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

Regulation of tyrosine hydroxylase by stress‐activated protein kinases

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