Tau kinases and phosphatases

Ávila, Jesús

doi:10.1111/j.1582-4934.2007.00214.x

Cited by 43 publications

(25 citation statements)

References 23 publications

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“…In the brains of AD patients, tau is hyperphosphorylated at 20–40 sites (Duka et al, ). The kinases that have been shown to phosphorylate tau include GSKIIIβ, MARK, MAPK, JNK1, PKA, ERKs, DYRK1a, casein kinase I, and cyclin‐dependent kinase‐5 (CDK5) (Avila, ; Hanger et al, ). Similar to other MAPs reviewed here, it has been demonstrated that tau phosphorylation reduces its affinity for microtubules or its ability to promote microtubule polymerization, resulting in overall microtubule instability (Avila et al, ).…”

Section: Introductionmentioning

confidence: 99%

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Ramkumar

Jong

Ori-McKenney

2017

Developmental Dynamics

151

111

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Classical microtubule-associated proteins (MAPs) were originally identified based on their co-purification with microtubules assembled from mammalian brain lysate. They have since been found to perform a range of functions involved in regulating the dynamics of the microtubule cytoskeleton. Most of these MAPs play integral roles in microtubule organization during neuronal development, microtubule remodeling during neuronal activity, and microtubule stabilization during neuronal maintenance. As a result, mutations in MAPs contribute to neurodevelopmental disorders, psychiatric conditions, and neurodegenerative diseases. MAPs are post-translationally regulated by phosphorylation depending on developmental time point and cellular context. Phosphorylation can affect the microtubule affinity, cellular localization, or overall function of a particular MAP and can thus have profound implications for neuronal health. Here we review MAP1, MAP2, MAP4, MAP6, MAP7, MAP9, tau, and DCX, and how each is regulated by phosphorylation in neuronal physiology and disease. Developmental Dynamics 247:138-155,

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Section: Introductionmentioning

confidence: 99%

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Ramkumar

Jong

Ori-McKenney

2017

Developmental Dynamics

151

111

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“…Tau phosphorylation state is regulated by site-specific dephosphorylation through certain phosphatases and by kinases phosphorylating tau protein at specific sites. Protein phosphatase 2A (PP2A) is the major phosphatase with 70% tau phosphatase activity in human brains [103]. This implies a protective role of PP2A in neurodegeneration which is consistent with the finding that PP2A activity is reduced in AD brains [104,105].…”

Section: Ir/igf-1r Signaling Alters Tau Phosphory-lationmentioning

confidence: 67%

The Role of IGF-1 Receptor and Insulin Receptor Signaling for the Pathogenesis of Alzheimers Disease: From Model Organisms to Human Disease

Freude

Schilbach²,

Schubert³

2009

CAR

127

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In different clinical studies, an association of type 2 diabetes and Alzheimer's disease (AD) has been described. However, the underlying mechanisms are still unclear. One explanation could be that vascular complications of diabetes result in neurodegeneration. Alternatively, the mechanism might be directly related to insulin and insulin-like growth factor(IGF)-1 signaling, leading to the proposal that AD is a "brain-type diabetes". Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration. These findings raise the question, whether this phenomenon is cause or consequence of neurodegeneration. Recently, Cohen and coworkers have show that knocking down DAF-2 in C. elegans, the homolog of the mammalian IR/IGF-1R, reduces beta-amyloid(Abeta)(1-42) toxicity. Cell based experiments suggest a specific role for the IGF 1/IRS-2 signaling pathway in regulating alpha-/beta-secretase activity. Moreover circulating IGF-1 might influence Abeta clearance from the brain by promoting Abeta transport over the blood brain barrier. Interestingly, brain specific deletion of IRS-2 increases life span, suggesting that long term neuronal IGF-1R signaling might be harmful. Taken together, the data from humans and different model organisms indicate a role of IR/IGF-1R signaling in Abeta metabolism, and clearance as well as longevity. Since more studies are needed to elucidate the impact of insulin and/or IGF-1 treatment in AD, the time to propose these hormones as a potential treatment option for AD has not come yet.

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“…The specific phosphorylation of Ser/Thr residues that precede a proline residue regulate tau function, such as binding to MT . Although phosphorylation of tau plays a critical role, abnormal hyper‐phosphorylation induces phosphorylation dependent conformational changes of tau, resulting in self‐association to form NFTs . Recent experimental studies show that phosphorylation of Thr 231 , a residue in the proline rich P2 domain (Fig.…”

Section: Introductionmentioning

confidence: 99%

Loss of intramolecular electrostatic interactions and limited conformational ensemble may promote self-association ofcis-tau peptide

Barman

Hamelberg

2015

Proteins

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Self-association of proteins can be triggered by a change in the distribution of the conformational ensemble. Posttranslational modification, such as phosphorylation, can induce a shift in the ensemble of conformations. In the brain of Alzheimer's disease patients, the formation of intra-cellular neurofibrillary tangles deposition is a result of self-aggregation of hyper-phosphorylated tau protein. Biochemical and NMR studies suggest that the cis peptidyl prolyl conformation of a phosphorylated threonine-proline motif in the tau protein renders tau more prone to aggregation than the trans isomer. However, little is known about the role of peptidyl prolyl cis/trans isomerization in tau aggregation. Here, we show that intra-molecular electrostatic interactions are better formed in the trans isomer. We explore the conformational landscape of the tau segment containing the phosphorylated-Thr(231)-Pro(232) motif using accelerated molecular dynamics and show that intra-molecular electrostatic interactions are coupled to the isomeric state of the peptidyl prolyl bond. Our results suggest that the loss of intra-molecular interactions and the more restricted conformational ensemble of the cis isomer could favor self-aggregation. The results are consistent with experiments, providing valuable complementary atomistic insights and a hypothetical model for isomer specific aggregation of the tau protein.

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Tau kinases and phosphatases

Cited by 43 publications

References 23 publications

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

The Role of IGF-1 Receptor and Insulin Receptor Signaling for the Pathogenesis of Alzheimers Disease: From Model Organisms to Human Disease

Loss of intramolecular electrostatic interactions and limited conformational ensemble may promote self-association ofcis-tau peptide

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