Altered Protein Tyrosine Phosphorylation in Alzheimer's Disease

Shapiro, Igor; Masliah, Eliezer; Saitoh, Tsunao

doi:10.1111/j.1471-4159.1991.tb11405.x

Cited by 60 publications

(21 citation statements)

References 49 publications

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“…Neuritic plaques and dystrophic neurites in AD brains contain a large amount of phosphotyrosine (pTyr) (Masliah et al, 1991; Shapiro et al, 1991), and cultured cells exposed to Aβ show higher levels of pTyr proteins (Bamberger et al, 2003; Grace and Busciglio, 2003; Matrone et al, 2009). Additionally an abnormally enhanced APP phosphorylation on Tyr residues has been previously reported in AD brain (Russo et al, 2001; Rebelo et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients

Poulsen

Iannuzzi

Rasmussen

et al. 2017

Front. Mol. Neurosci.

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Alzheimer's disease (AD) is the most common cause of dementia and is likely caused by defective amyloid precursor protein (APP) trafficking and processing in neurons leading to amyloid plaques containing the amyloid-β (Aβ) APP peptide byproducts. Understanding how APP is targeted to selected destinations inside neurons and identifying the mechanisms responsible for the generation of Aβ are thus the keys for the advancement of new therapies. We previously developed a mouse model with a mutation at tyrosine (Tyr) 682 in the C-terminus of APP. This residue is needed for APP to bind to the coating protein Clathrin and to the Clathrin adaptor protein AP2 as well as for the correct APP trafficking and sorting in neurons. By extending these findings to humans, we found that APP binding to Clathrin is decreased in neural stem cells from AD sufferers. Increased APP Tyr phosphorylation alters APP trafficking in AD neurons and it is associated to Fyn Tyr kinase activation. We show that compounds affecting Tyr kinase activity and counteracting defects in AD neurons can control APP location and compartmentalization. APP Tyr phosphorylation is thus a potential therapeutic target for AD.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients

Poulsen

Iannuzzi

Rasmussen

et al. 2017

Front. Mol. Neurosci.

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“…Our data now suggest that this could result in increased activation of SFK in the course of neuropathogenesis. It has been reported that AD brains have an increase in tyrosine phosphorylated proteins (Shapiro et al, 1991) as well as altered localizations of Fyn and Src (Ho et al, 2005;Shirazi and Wood, 1993). An increase in SFK activity would impact on synaptic transmission and plasticity (reviewed by Kalia et al, 2004) and evidence for the role of Fyn in synaptotoxicity in AD has been obtained using mouse models (Chin et al, 2005; Chin et al, 2004).…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

Tau impacts on growth-factor-stimulated actin remodeling

Sharma

Litersky

Bhaskar

et al. 2007

Journal of Cell Science

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The microtubule-associated protein tau interacts with the SH3 domain of non-receptor Src family protein tyrosine kinases. A potential consequence of the SH3 interaction is the upregulation of tyrosine kinase activity. Here we investigated the activation of Src or Fyn by tau, both in vitro and in vivo. Tau increased the kinase activity in in vitro assays and in transfected COS7 cells. In plateletderived growth factor (PDGF)-stimulated fibroblasts, tau appeared to prime Src for activation following PDGF stimulation, as reflected by changes in Src-mediated actin rearrangements. In addition, while fibroblasts normally recovered actin stress fibers by 5-7 hours after PDGF stimulation, tau-expressing cells showed sustained actin breakdown. Microtubule association by tau was not required for the observed changes in actin morphology. Inhibition of Src kinases or a mutant deficient in Src interaction reduced the effects, implicating Src family protein tyrosine kinases as a mediator of the effects of tau on actin rearrangements. Our results provide evidence that the interaction of tau with Src upregulates tyrosine kinase activity and that this interaction allows tau to impact on growth-factor-induced actin remodeling. Journal of Cell Science Tau impacts on actin remodeling Results Tau affects SFK activityWe have previously shown through in vitro binding assays that human tau interacted with the SH3 domain of Fyn and Src (Bhaskar et al., 2005;Lee et al., 1998). Based on the crystal structure of Src, SH3 ligands are thought to 'unclamp' an inactive form of Src, enhancing its activation (Xu et al., 1999;Xu et al., 1997). Our first indication that tau might function in this manner came from experiments initially performed to examine the ability of tyrosine-phosphorylated tau to associate with microtubules. Purified tau and Fyn were incubated in an in vitro kinase reaction to first generate tyrosinephosphorylated tau. The reaction was then added to taxolstabilized microtubules. Upon examining the microtubule pellet for tyrosine-phosphorylated tau, we discovered that the taxol-stabilized tubulin was also tyrosine phosphorylated, presumably by the Fyn that had been carried over from the kinase reaction. Moreover, although Fyn alone was capable of phosphorylating taxol-stabilized microtubules, the presence of tau greatly enhanced the phosphorylation (Fig. 1A, compare lanes 4 and 8).However, because tau binds to microtubules, a possible explanation for the enhanced tubulin phosphorylation was that tau was simply bringing Fyn to the microtubules and facilitating tubulin phosphorylation without affecting Fyn activity. This would predict that a fragment of tau lacking microtubule-binding activity would be incapable of enhancing the phosphorylation. We therefore tested an N-terminal fragment of tau that binds to Fyn SH3 but lacks the microtubule-binding repeats [amino acids 1-184 (Lee et al., 1998)]. By using the same protocol in which the tau fragment was incubated with Fyn and then added to taxol-stabilized microtubules, we found ...

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“…In addition, several other studies have suggested a role for tyrosine phosphorylation in AD. AD brains showed an increase in phosphotyrosine-containing proteins (Shapiro et al, 1991), and cultured cells exposed to A␤ contained higher levels of tyrosine phosphorylated proteins (Luo et al, 1995;Moore et al, 2002;Bamberger et al, 2003;Grace and Busciglio, 2003). Tyrosine phosphorylation of paxillin (Grace and Busciglio, 2003), tau (Williamson et al, 2002), and several protein kinases, including focal adhesion kinase (Zhang et al, 1994;Williamson et al, 2002), MAP kinase (Sato et al, 1997), and phosphatidylinositol 3-kinase (Luo et al, 1996), increase in the presence of A␤.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease

Lee¹,

Thangavel²,

Sharma³

et al. 2004

J. Neurosci.

376

349

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The abnormal phosphorylation of tau protein on serines and threonines is a hallmark characteristic of the neurofibrillary tangles of Alzheimer's disease (AD). The discovery that tau could be phosphorylated on tyrosine and evidence that A␤ signal transduction involved tyrosine phosphorylation led us to question whether tyrosine phosphorylation of tau occurred during the neurodegenerative process. In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. By developing both polyclonal and monoclonal probes specific for phospho-tyr18, we found that the phosphorylation of tau at tyr18 occurred at early developmental stages in mouse but was absent in the adult. Our phosphospecific probes also revealed that paired helical filament preparations exhibited phospho-tyr18 reactivity that was sensitive to phosphotyrosine-specific protein phosphatase treatment. Moreover, immunocytochemical studies indicated that tyrosine phosphorylated tau was present in the neurofibrillary tangles in AD brain. However, the staining pattern excluded neuropil threads and dystrophic neurites indicating that tyrosine phosphorylated tau was distributed in AD brain in a manner dissimilar from other abnormally phosphorylated tau. We also found evidence suggesting that differentially phosphorylated tau existed within degenerating neurons. Our data add new support for a role for fyn in the neurodegenerative process.

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Altered Protein Tyrosine Phosphorylation in Alzheimer's Disease

Cited by 60 publications

References 49 publications

RETRACTED: An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients

RETRACTED: An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients

Tau impacts on growth-factor-stimulated actin remodeling

Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease

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