Involvement of 14‐3‐3 in tubulin instability and impaired axon development is mediated by Tau

Joo, Yeon Ho; Schumacher, Benjamin; Landrieu, Isabelle; Bartel, Maria; Smet‐Nocca, Caroline; Jang, Ahram; Choi, Hee Soon; Jeon, Noo Li; Chang, Keun A.; Kim, Hye Sun; Ottmann, C.; Suh, Yoo‐Hun

doi:10.1096/fj.14-265009

Cited by 69 publications

(111 citation statements)

References 57 publications

(82 reference statements)

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“…We then characterized the interaction of MAP2c with 14-3-3 at a molecular level, and we studied the effect of 14-3-3 on tubulin polymerization induced by MAP2c. We found that the same regions of unphosphorylated MAP2c and Tau interact with 14-3-3 and that the binding affinity of MAP2c is greatly increased by phosphorylation, as described previously for Tau (25,39). However, NMR analysis of the phosphorylation kinetics revealed that, despite their highly homologous sequences, PKA phosphorylates MAP2c and Tau in a different manner.…”

supporting

confidence: 82%

“…14-3-3 proteins are proposed to be involved in the phosphorylation-dependent control of microtubule dynamics by competing for phosphorylated Tau with tubulin (24,39,40). PKA seems to be the key kinase in this mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated forms of both MAP2c and Tau seem to interact with 14-3-3 proteins predominantly via two phosphoserines, one located in the proline-rich domain (25,27,39) and the other in the C-terminal portion (27, 39). As discussed above, the phosphorylation sites of MAP2c and Tau differ significantly even in regions of high sequential homology, which has a direct impact on phosphorylation-dependent 14-3-3 binding.…”

Section: Phosphorylation Of Map2c and Interaction With 14-3-3mentioning

confidence: 99%

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Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Jansen

Melková

Trošanová

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellMicrotubule-associated protein 2c (MAP2c) is involved in neuronal development and is less characterized than its homolog Tau, which has various roles in neurodegeneration. Using NMR methods providing single-residue resolution and quantitative comparison, we investigated molecular interactions important for the regulatory roles of MAP2c in microtubule dynamics. We found that MAP2c and Tau significantly differ in the position and kinetics of sites that are phosphorylated by cAMP-dependent protein kinase (PKA), even in highly homologous regions. We determined the binding sites of unphosphorylated and phosphorylated MAP2c responsible for interactions with the regulatory protein 14-3-3 . Differences in phosphorylation and in charge distribution between MAP2c and Tau suggested that both MAP2c and Tau respond to the same signal (phosphorylation by PKA) but have different downstream effects, indicating a signaling branch point for controlling microtubule stability. Although the interactions of phosphorylated Tau with 14-3-3 are supposed to be a major factor in microtubule destabilization, the binding of 14-3-3 to MAP2c enhanced by PKA-mediated phosphorylation is likely to influence microtubule-MAP2c binding much less, in agreement with the results of our tubulin co-sedimentation measurements. The specific location of the major MAP2c phosphorylation site in a region homologous to the muscarinic receptor-binding site of Tau suggests that MAP2c also may regulate processes other than microtubule dynamics.Cytoskeletal microtubule-associated proteins (MAPs) 3 are proteins of critical importance for regulating the stability and dynamics of microtubules (1). MAP2 and Tau represent MAP subfamilies expressed in neurons; MAP2 is localized in dendrites, whereas Tau is found mainly in axons (2). Tau and MAP2 belong to the class of intrinsically disordered proteins (IDPs), which lack a unique structure and which exist in multiple, quickly interconverting conformations (3-7). NMR is the method of choice for structural investigation of this type of protein. Tau and MAP2 differ in their N-terminal projection domains, which contain acidic and proline-rich subdomains, whereas the C-terminal parts, containing the microtubulebinding domain (MTBD) and the C-terminal region, are homologous (8). Tau is expressed in several splice variants. The human brain isoforms differ in the number of microtubulebinding regions (MTBRs) in the C-terminal portion and in the presence of two inserts near the N terminus. For the sake of simplicity, only the 441-residue variant lacking exons 6, 8, and 10 (9) is discussed in this paper. This variant has been studied in detail and was shown to form paired helical filaments and neurofibillary tangles in brains of patients suffering from Alzheimer's disease (10). The MAP2 family is composed of two high-molecular-weight proteins, MAP2a and MAP2b, each consisting of 1830 amino acids, and two low-molecular-weight proteins, MAP2c and MAP2d, consisting of 467 and 498 amino acids, respectively. The ...

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supporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Phosphorylation Of Map2c and Interaction With 14-3-3mentioning

confidence: 99%

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Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Jansen

Melková

Trošanová

et al. 2017

Journal of Biological Chemistry

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“…Moreover, our results (Figs. 3B and 3C) showed that the diabetic pathophysiological factors could upregulate ROCK1 and 14-3-3σ which are associated with neurodegeneration [32, 33]. Thus it would be interesting to investigate whether ROCK1 or 14-3-3σ is a link between type 2 diabetes and Alzheimer's disease which shows an increased risk in type 2 diabetes [34].…”

Section: Discussionmentioning

confidence: 99%

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Wang¹,

Lü²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Type 2 diabetes is associated with oxidative stress and DNA damage which can cause centrosome amplification. Thus, the study investigated centrosome amplification in type 2 diabetes and the underlying mechanisms. Methods: Centrosome numbers in human peripheral blood mononuclear blood cells (PBMC) from healthy subjects and patients with type 2 diabetes were compared to access the association between type 2 diabetes and centrosome amplification. Colon cancer cells were used to investigate the molecular mechanisms underlying the centrosome amplification triggered by high glucose, insulin and palmitic acid. Western blot analysis was used to quantify the level of protein and protein phosphorylation. Immunofluorescent staining was performed to detect centrosomes. ROS was quantified using flow cytometry technique. Transcriptpmic profiling was performed using Illumina HiSeq^TM500 platform. Results: We found that centrosome amplification was increased PBMC from the type 2 diabetic patients, which correlated with the levels of fasting blood glucose and HbA1c. High glucose, insulin and palmitic acid, alone or in combinations, induced ROS production and centrosome amplification. Together, they increased AKT activation as well as the expression, binding and centrosome translation of ROCK1 and 14-3-3σ. Results from further analyses showed that AKT-ROS-dependent upregulations of expression, binding and centrosome translocation of ROCK1 and 14-3-3σ was the molecular pathway underlying the centrosome amplification in vitro triggered by high glucose, insulin and palmitic acid. Moreover, the key in vitro molecular signalling events activated by high glucose, insulin and palmitic acid were verified in PBMC from the patients with type 2 diabetes. Conclusion: Our results show that type 2 diabetes promotes cell centrosome amplification, and suggest that the diabetic pathophysiological factors-activated AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ is the underlying molecular mechanism.

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“…118,119 Previously, we solved the crystal structure of 14-3-3 in complex with synthetic peptides comprising the phosphorylation sites pSer214 and pSer324. 120 The sequence surrounding pSer214 ( 211 RTPpSLPTP 218 ) is especially interesting with three proline residues as notable structural features ( Figure 8A). In particular, Pro218 occupies a position that is not used by most of the other structurally elucidated 14-3-3 recognition motifs.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

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Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein−protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

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Involvement of 14‐3‐3 in tubulin instability and impaired axon development is mediated by Tau

Abstract: 14-

Cited by 69 publications

References 57 publications

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3σ

Modulators of Protein–Protein Interactions

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