Regulation of S6 Kinase 1 Activation by Phosphorylation at Ser-411

Hou, Zhibo; He, Lisheng; Qi, Robert Z.

doi:10.1074/jbc.m607836200

Cited by 30 publications

(27 citation statements)

References 40 publications

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“…We also investigated the role of p35 in neurite formation. In PC12 cultures, application of GW8510, a specific Cdk5 inhibitor compound of low cytotoxicity (41,42), effectively inhibited NGF-induced neurite outgrowth (Fig. 6, A and B), in agreement with the reported observations using roscovitine or the kinase-dead Cdk5 mutants (12,14,39,40).…”

Section: Effects Of P35 Phosphorylation On Its Microtubule-polymerizisupporting

confidence: 90%

Calmodulin Binding and Cdk5 Phosphorylation of p35 Regulate Its Effect on Microtubules

Hou

2008

Journal of Biological Chemistry

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In the nervous system, Cdk5 and its neuronal activator p35 are involved in the control of various activities, including neuronal differentiation and migration. Recently, we have reported that p35 is a microtubule-associated protein that regulates microtubule dynamics ( 2؉ -specific manner, suggesting that p35 may be involved in the Ca 2؉ /CaMmediated inhibition of microtubule assembly. Second, p35 phosphorylation by Cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at Thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity. In PC12 cells, expression of p35 promotes nerve growth factor-induced neurite outgrowth under a Cdk5 inhibitory condition. Such p35 activity is impaired by the phosphomimetic mutation of Thr-138. These data suggest that Thr-138 phosphorylation plays a critical role in the control of the p35 functions in microtubule assembly and neurite outgrowth.

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Section: Effects Of P35 Phosphorylation On Its Microtubule-polymerizisupporting

confidence: 90%

Calmodulin Binding and Cdk5 Phosphorylation of p35 Regulate Its Effect on Microtubules

Hou

2008

Journal of Biological Chemistry

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“…Indeed, recent evidence has demonstrated that both CDK1 and CDK5 have the potential to phosphorylate S6K1 directly. In the case of CDK5, phosphorylation of S6K1 on Thr 411 has been demonstrated to be required for its phosphorylation and activation by mTOR, suggesting that such a feedback loop between CDK2 and S6K1 may exist in cycling T cells (58,59). That S6 is itself important for T cell proliferation has been established in mice expressing one defective allele for S6 (60).…”

Section: Discussionmentioning

confidence: 99%

A Fas-Associated Death Domain Protein/Caspase-8-Signaling Axis Promotes S-Phase Entry and Maintains S6 Kinase Activity in T Cells Responding to IL-2

Arechiga

Bell

Leverrier

et al. 2007

The Journal of Immunology

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Fas-associated death domain protein (FADD) constitutes an essential component of TNFR-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. In this study, we report that FADD is necessary for long-term maintenance of S6 kinase (S6K) activity. S6 phosphorylation at serines 240 and 244 was only observed after long-term stimulation of wild-type cells, roughly corresponding to the time before S-phase entry, and was poorly induced in T cells expressing a dominantly interfering form of FADD (FADDdd), viral FLIP, or possessing a deficiency in caspase-8. Defects in S6K1 phosphorylation were also observed. However, defective S6K1 phosphorylation was not a consequence of a wholesale defect in mammalian target of rapamycin function, because 4E-BP1 phosphorylation following T cell activation was unaffected by FADDdd expression. Although cyclin D3 up-regulation and retinoblastoma hypophosphorylation occurred normally in FADDdd T cells, cyclin E expression and cyclin-dependent kinase 2 activation were markedly impaired in FADDdd T cells. These results demonstrate that a FADD/caspase-8-signaling axis promotes T cell cycle progression and sustained S6K activity.

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“…A variety of reporters can be used to quantify activity in this pathway; Abl‐mediated Cdk5/p35 activity, detected from the S6K‐pSer 411 immunoreactivity (Hou et al. 2007), was significantly different between WT and WIP −/− neurons (Fig. 3A and B).…”

Section: Resultsmentioning

confidence: 89%

“…2000; Hou et al. 2007). To test whether reduced Abl activity is responsible for the differences observed between WIP −/− and WT neurons, we cultured primary neurons from both genotypes alone, with the Abl inhibitor imatinib, or with DMSO.…”

Section: Resultsmentioning

confidence: 99%

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Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

Franco-Villanueva

Antón

2015

Brain and Behavior

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IntroductionNeuronal morphogenesis is governed mainly by two interconnected processes, cytoskeletal reorganization, and signal transduction. The actin‐binding molecule WIP (Wiskott‐Aldrich syndrome protein [WASP]‐interacting protein) was identified as a negative regulator of neuritogenesis. Although WIP controls activity of the actin‐nucleation‐promoting factor neural WASP (N‐WASP) during neuritic differentiation, its implication in signal transduction remains unknown.MethodsUsing primary neurons from WIP‐deficient and wild‐type mice we did an immunofluorescence, morphometric, and biochemical analysis of the signaling modified by WIP deficiency.ResultsHere, we describe the WIP contribution to the regulation of neuritic elaboration and ramification through modification in phosphorylation levels of several kinases that participate in the mammalian target of rapamycin complex 1 (mTORC1)‐p70S6K (phosphoprotein 70 ribosomal protein S6 kinase, S6K) intracellular signaling pathway. WIP deficiency induces an increase in the number of neuritic bifurcations and filopodial protrusions in primary embryonic neurons. This phenotype is not due to modifications in the activity of the phosphoinositide 3 kinase (PI3K)‐Akt pathway, but to reduced phosphorylation of the S6K residues Ser411 and Thr389. The resulting decrease in kinase activity leads to reduced S6 phosphorylation in the absence of WIP. Incubation of control neurons with pharmacological inhibitors of mTORC1 or Abl, two S6K regulators, conferred a morphology resembling that of WIP‐deficient neurons. Moreover, the preferential co‐distribution of phospho‐S6K with polymerized actin is altered in WIP‐deficient neurons.ConclusionThese experiments identify WIP as a member of a signaling cascade comprised of Abl family kinases, mTORC1 and S6K, which regulates neuron development and specifically, neuritic branching and complexity. Thus, we postulated a new role for WIP protein.

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Regulation of S6 Kinase 1 Activation by Phosphorylation at Ser-411

Cited by 30 publications

References 40 publications

Calmodulin Binding and Cdk5 Phosphorylation of p35 Regulate Its Effect on Microtubules

Calmodulin Binding and Cdk5 Phosphorylation of p35 Regulate Its Effect on Microtubules

A Fas-Associated Death Domain Protein/Caspase-8-Signaling Axis Promotes S-Phase Entry and Maintains S6 Kinase Activity in T Cells Responding to IL-2

Neuritic complexity of hippocampal neurons depends on WIP‐mediated mTORC1 and Abl family kinases activities

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