Atypical protein kinase Cλ binds and regulates p70 S6 kinase

Akimoto, Kazunori; Nakaya, Muneo; Yamanaka, Tatsuhiko; Tanaka, Jumpei; Matsuda, Shin Ichi; Weng, Qing; Avruch, Joseph; Ohno, Shigeo

doi:10.1042/bj3350417

Cited by 73 publications

(56 citation statements)

References 58 publications

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“…Atypical PKCs, specifically PKCl and PKCz, have been shown to regulate p70S6K phosphorylation and activity (Akimoto et al, 1998;Romanelli et al, 1999). Depletion of intracellular stores of Ca 2+ has been shown to abolish p70S6K activation, but has no effect on AKT activation (Conus et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis

Hittelman

Liu

et al. 2003

Oncogene

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The 70 kDa ribosomal S6 kinase (p70S6K) is important for cell growth and survival. Activation of p70S6K requires sequential phosphorylation of multiple serine and threonine sites often triggered by growth factors and hormones. Here, we report that paclitaxel, a microtubuledamaging agent, induces phosphorylation of p70S6K at threonine 421 and serine 424 (T421/S424) in a concentration-and time-dependent manner in multiple breast and ovarian cancer cell lines demonstrated by a T421/S424 phospho-p70S6K antibody. Phosphoamino-acid analysis and Western blot analysis by serine-/threonine-specific antibodies further confirms that both serine and threonine residues are phosphorylated in p70S6K following treatment with paclitaxel. Paclitaxel-induced p70S6K T421/S424 phosphorylation requires both de novo RNA and protein synthesis via multiple signaling pathways including ERK1/2 MAP kinase, JNK, PKC, Ca ++ , PI3K, and mammalian target of rapamycin (mTOR). Despite phosphorylation of p70S6K T421/S424 , paclitaxel inactivates this kinase in a concentration-and time-dependent manner as illustrated by in vitro kinase assay. Inhibitors of mTOR, PI3K, and Ca ++ impair p70S6K activity, whereas inhibitors of JNK and PKC stimulate p70S6K activity. Inhibition of PKC and JNK prevents paclitaxelinduced p70S6K inactivation. Moreover, the paclitaxelinduced phosphorylation and low activity of p70S6K mainly occurs during mitosis. In summary, paclitaxel is able to induce p70S6K T421/S424 phosphorylation and decrease its activity in mitotic cells via multiple signaling pathways. Our data suggest that paclitaxel-induced p70S6K T421/S424 phosphorylation and kinase inactivation are differentially regulated. Our data also indicate that paclitaxel may exert its antitumor effect, at least in part, via inhibition of p70S6K.

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Section: Discussionmentioning

confidence: 99%

Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis

Hittelman

Liu

et al. 2003

Oncogene

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“…The isoforms are divided into three subgroups; conventional, Ca 2ϩ -responsive PKC, the novel, Ca 2ϩ -unresponsive PKC, and the atypical, Ca 2ϩ -and TPA-unresponsive PKC (52). Recently, p70 S6k has been shown to be regulated by TPA-responsive (16,29) and -unresponsive PKC isoforms (53,54). In addition, it has been reported that PKC isoforms, including ␣, ␤I, and ␥ of conventional PKC, ␦ and ⑀ of novel PKC, and of atypical PKC, are tyrosine phosphorylated and catalytically activated by treatment of cells with H 2 O 2 (55).…”

Section: Role Of H 2 O 2 In P70mentioning

confidence: 99%

Hydrogen Peroxide Activates p70S6k Signaling Pathway

Bae

Seo

Kwon

et al. 1999

Journal of Biological Chemistry

137

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“…Both kinases receive an input signal from common effectors of the PI3-K pathway, including PDK1, protein kinase B, PKC, Rac, and CDC42 (1,6,9,32,47,50). However, some differences in the regulation of S6K␣ and S6K␤ have started to emerge.…”

mentioning

confidence: 99%

“…Furthermore, prolonged treatment of cells with PMA, which leads to down-regulation of DAG-activated PKCs, eliminates mitogenic activation of S6K␣ (56,57). Recently, the PI3-K-and PDK1-activated atypical PKC isoforms and have been implicated in the regulation of S6K␣ (1,31,50). Atypical PKCs have been found in complexes with S6K␣, but it is not yet known whether they can directly phosphorylate and modulate the function of S6Ks.…”

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confidence: 99%

Protein Kinase C Phosphorylates Ribosomal Protein S6 Kinase βII and Regulates Its Subcellular Localization

Valovka

Verdier

Cramer

et al. 2003

Molecular and Cellular Biology

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The ribosomal protein S6 kinase (S6K) belongs to the AGC family of Ser/Thr kinases and is known to be involved in the regulation of protein synthesis and the G 1 /S transition of the cell cycle. There are two forms of S6K, termed S6K␣ and S6K␤, which have cytoplasmic and nuclear splice variants. Nucleocytoplasmic shuttling has been recently proposed for S6K␣, based on the use of the nuclear export inhibitor, leptomycin B. However, the molecular mechanisms regulating subcellular localization of S6Ks in response to mitogenic stimuli remain to be elucidated. Here we present data on the in vitro and in vivo phosphorylation of S6K␤, but not S6K␣, by protein kinase C (PKC). The site of phosphorylation was identified as S486, which is located within the C-terminal nuclear localization signal. Mutational analysis and the use of phosphospecific antibodies provided evidence that PKC-mediated phosphorylation at S486 does not affect S6K activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. Taken together, this study uncovers a novel mechanism for the regulation of nucleocytoplasmic shuttling of S6K␤II by PKC-mediated phosphorylation.The ribosomal protein S6 (rpS6) kinase (S6K) belongs to the AGC family of Ser/Thr protein kinases which includes the protein kinase C's (PKCs), protein kinase B's, SGKs, and 90-kDa ribosomal S6 kinases (p90 RSKs). There are two forms of S6K, S6K␣ and S6K␤, which have cytoplasmic (S6K␣II and S6K␤II) and nuclear (S6K␣I and S6K␤I) variants derived from alternative splicings at the N terminus (2, 15). S6K␣ and S6K␤ have a very high level of overall sequence similarity, with the greatest homology in the kinase and kinase extension domains. However, both kinases differ significantly at their N-and Cterminal regulatory regions, sharing only 28 and 25% homology, respectively. The C terminus of S6K␤ contains a specific proline-rich region, which is absent in S6K␣ and might be involved in mediating protein-protein interactions with SH3 and WW domain-containing molecules. The presence of a PDZ domain-binding motif at the C terminus of S6K␣ may direct the kinase into distinct signaling complexes (8).The activity of S6K is regulated by phosphorylation and dephosphorylation events in cellular responses to various extracellular stimuli. The treatment of cells with growth factors, cytokines, and hormones leads to a rapid activation of S6K (10), while growth inhibitory agents, such as steroids and transforming growth factor ␤, suppress kinase activity (45, 52). The mechanism of activation of S6K␣ has been studied in detail by various laboratories and was shown to be a multistep phosphorylation process involving several Ser/Thr kinases (14,64).No direct, highly specific S6K inhibitor has yet been identified. Under these circumstances, the use of two indirect inhibitors, namely wortmannin (a phosphatidylinositol 3-kinase [PI3-K] inhibitor) and rapamycin (an mTOR inhibitor), has been instrumental in dissecting signaling even...

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Atypical protein kinase Cλ binds and regulates p70 S6 kinase

Cited by 73 publications

References 58 publications

Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis

Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis

Hydrogen Peroxide Activates p70S6k Signaling Pathway

Protein Kinase C Phosphorylates Ribosomal Protein S6 Kinase βII and Regulates Its Subcellular Localization

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