Post-translational modifications regulate microtubule function

Westermann, Stefan; Weber, Klaus

doi:10.1038/nrm1260

Cited by 642 publications

(564 citation statements)

References 104 publications

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“…15,[23][24][25] To assess whether this function may involve the stabilization of midbody microtubules, we measured the ratio of acetylated versus tyrosinated α-tubulin at the midbody of control cells and of cells lacking CIT-K. 28 Indeed, dynamic microtubules contain a relatively high amount of α-tubulin tyrosinated at its carboxyterminus, whereas stable microtubules show a high content of α-tubulin acetylated at the K40 residue. 29 We studied two cellular models characterized by different sensitivity to CIT-K loss and by different physiological relevance: cultures of proliferating neocortical neuronal progenitors obtained from control or from Cit-K knockout mice at embryonic day (E)12.5 and HeLa cells depleted of CIT-K by RNAi. In both models cytokinesis fails after cells have reached the midbody stage, with a penetrance of ∼ 90% in the case of neuronal progenitors and of 30% in the case of HeLa cells (Gai et al 23 and data not shown).…”

Section: Resultsmentioning

confidence: 99%

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

et al. 2015

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Cytokinesis, the physical separation of daughter cells at the end of cell cycle, is commonly considered a highly stereotyped phenomenon. However, in some specialized cells this process may involve specific molecular events that are still largely unknown. In mammals, loss of Citron-kinase (CIT-K) leads to massive cytokinesis failure and apoptosis only in neuronal progenitors and in male germ cells, resulting in severe microcephaly and testicular hypoplasia, but the reasons for this specificity are unknown. In this report we show that CIT-K modulates the stability of midbody microtubules and that the expression of tubulin β-III (TUBB3) is crucial for this phenotype. We observed that TUBB3 is expressed in proliferating CNS progenitors, with a pattern correlating with the susceptibility to CIT-K loss. More importantly, depletion of TUBB3 in CIT-K-dependent cells makes them resistant to CIT-K loss, whereas TUBB3 overexpression increases their sensitivity to CIT-K knockdown. The loss of CIT-K leads to a strong decrease in the phosphorylation of S444 on TUBB3, a post-translational modification associated with microtubule stabilization. CIT-K may promote this event by interacting with TUBB3 and by recruiting at the midbody casein kinase-2α (CK2α) that has previously been reported to phosphorylate the S444 residue. Indeed, CK2α is lost from the midbody in CIT-K-depleted cells. Moreover, expression of the nonphosphorylatable TUBB3 mutant S444A induces cytokinesis failure, whereas expression of the phospho-mimetic mutant S444D rescues the cytokinesis failure induced by both CIT-K and CK2α loss. Altogether, our findings reveal that expression of relatively low levels of TUBB3 in mitotic cells can be detrimental for their cytokinesis and underscore the importance of CIT-K in counteracting this event.

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Section: Resultsmentioning

confidence: 99%

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

et al. 2015

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“…Detecting the presence of post-translational modifications on proteins and quantifying their abundance are prerequisites for understanding many biological processes [1][2][3]. Despite the availability of an array of techniques for the elucidation of post-translational modifications [4][5][6], their study continues to present a formidable analytical challenge.…”

Section: Introductionmentioning

confidence: 99%

A novel high-capacity ion trap-quadrupole tandem mass spectrometer

Krutchinsky¹,

Cohen

Chait

2007

International Journal of Mass Spectrometry

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We describe a prototype tandem mass spectrometer that is designed to increase the efficiency of linked-scan analyses by >100-fold over conventional linked-scan instruments. The key element of the mass spectrometer is a novel high ion capacity ion trap, combined in tandem configuration with a quadrupole collision cell and a quadrupole mass analyzer (i.e. a TrapqQ configuration). This ion trap can store >10 6 ions without significant degradation of its performance. The current mass resolution of the trap is 100-450 full width at half maximum for ions in the range 800-4000 m/z, yielding a 10-20 m/z selection window for ions ejected at any given time into the collision cell. The sensitivity of the mass spectrometer for detecting peptides is in the low femtomole range. We can envisage relatively straightforward modifications to the instrument that should improve both its resolution and sensitivity. We tested the tandem mass spectrometer for collecting precursor ion spectra of all the ions stored in the trap and demonstrated that we can selectively detect a phosphopeptide in a mixture of non-phosphorylated peptides. Based on this prototype instrument, we plan to construct a fully functional model of the mass spectrometer for detecting modification sites on proteins and profiling their abundances with high speed and sensitivity.

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“…Analyses of our synthetic-lethality data suggest that Ber1 is involved in N-acetylation and/or proteasome biogenesis. Although tubulin acetylation was proposed to modulate microtubule dynamics in higher eukaryotes (Westermann and Weber 2003), this modiWcation has not (yet) been shown in yeast. Thus, our data indicate that Ber1 is involved in proper kinetochore function and perhaps other microtubule-related processes, and suggest that it might act through N-acetylation of one or several non-identiWed proteins.…”

Section: Introductionmentioning

confidence: 99%

The evolutionary conserved BER1 gene is involved in microtubule stability in yeast

et al. 2007

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In yeast, microtubules are dynamic Wlaments necessary for spindle and nucleus positioning, as well as for proper chromosome segregation. We identify a function for the yeast gene BER1 (Benomyl REsistant 1) in microtubule stability. BER1 belongs to an evolutionary conserved gene family whose founding member Sensitivity to Red light Reduced is involved in red-light perception and circadian rhythms in Arabidopsis. Here, we present data showing that the ber1 mutant is aVected in microtubule stability, particularly in presence of microtubuledepolymerising drugs. The pattern of synthetic lethal interactions obtained with the ber1 mutant suggests that Ber1 may function in N-terminal protein acetylation. Our work thus suggests that microtubule stability might be regulated through this post-translational modiWcation on yetto-be determined proteins.

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Post-translational modifications regulate microtubule function

Abstract: Long protrusions that contain a microtubular axoneme, the beating of which can drive a cell through liquid media. Note that bacterial flagella are constructed very differently from eukaryotic flagella. PROTISTS Single-celled eukaryotic organisms that are either free living or parasitic.

Cited by 642 publications

References 104 publications

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation

A novel high-capacity ion trap-quadrupole tandem mass spectrometer

The evolutionary conserved BER1 gene is involved in microtubule stability in yeast

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