Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor.

We have used the yeast two-hybrid system to identify proteins that interact with the intracellular portion of the hepatocyte growth factor (HGF) receptor (Met). We isolated a human cDNA encoding a novel protein of 68 kDa, which we termed FAP68. This protein is homologous to a previously described FK506-binding protein-associated protein, FAP48, which derives from an alternative spliced form of the same cDNA, lacking an 85-nucleotide exon and leading to an early stop codon. Here we show that epithelial cells, in which the HGF receptor is naturally expressed, contain FAP68 and not FAP48 proteins. FAP68 binding to Met requires the last 30 amino acids of the C-terminal tail, which are unique to the HGF receptor. Indeed, FAP68 does not interact with related tyrosine kinases of the Met and insulin receptor families. FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor. In vivo, endogenous FAP68 can be coimmunoprecipitated with the HGF receptor in the absence of stimuli and not upon HGF stimulation. Thus, FAP68 represents a novel type of effector that interacts with the inactive HGF receptor and is released upon receptor phosphorylation. Free FAP68 exerts a specific stimulatory activity toward the downstream target p70 S6 protein kinase (p70S6K). Significantly, nonphosphorylated HGF receptor prevents FAP68 from stimulating p70S6K. These data suggest a role for FAP68 in coupling HGF receptor signaling to the p70S6K pathway

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

The FK506-binding protein 52 (FKBP52) belongs to a large family of ubiquitously expressed and highly conserved proteins (FKBPs) that share an FKBP domain and possess Peptidyl-Prolyl Isomerase (PPIase) activity. PPIase activity catalyzes the isomerization of Peptidyl-Prolyl bonds and therefore influences target protein folding and function. FKBP52 is particularly abundant in the nervous system and is partially associated with the microtubule network in different cell types suggesting its implication in microtubule function. Various studies have focused on FKBP52, highlighting its importance in several neuronal microtubule-dependent signaling pathways and its possible implication in neurodegenerative diseases such as tauopathies (i.e., Alzheimer disease) and alpha-synucleinopathies (i.e., Parkinson disease). This review summarizes our current understanding of FKBP52 actions in the microtubule environment, its implication in neuronal signaling and function, its interactions with other members of the FKBPs family and its involvement in neurodegenerative disease

FKBP52 in Neuronal Signaling and Neurodegenerative Diseases: A Microtubule Story

International audienceThe FK506-binding protein 52 (FKBP52) belongs to a large family of ubiquitously expressed and highly conserved proteins (FKBPs) that share an FKBP domain and possess Peptidyl-Prolyl Isomerase (PPIase) activity. PPIase activity catalyzes the isomerization of Peptidyl-Prolyl bonds and therefore influences target protein folding and function. FKBP52 is particularly abundant in the nervous system and is partially associated with the microtubule network in different cell types suggesting its implication in microtubule function. Various studies have focused on FKBP52, highlighting its importance in several neuronal microtubule-dependent signaling pathways and its possible implication in neurodegenerative diseases such as tauopathies (i.e., Alzheimer disease) and alpha-synucleinopathies (i.e., Parkinson disease). This review summarizes our current understanding of FKBP52 actions in the microtubule environment, its implication in neuronal signaling and function, its interactions with other members of the FKBPs family and its involvement in neurodegenerative disease

The immunophilin FKBP52 specifically binds to tubulin and prevents microtubule formation.: FKBP52 and Tubulin Functional interaction.

The FK506 binding protein FKBP52 belongs to the large family of immunophilins and is known as a steroid receptor-associated protein. Previous data suggest that FKBP52 is associated with the motor protein dynein and with the cytoskeleton during mitosis. Here we demonstrate a specific and direct interaction between FKBP52 and tubulin. The region of FKBP52 located between aa 267 and 400, which includes the tetratricopeptide repeat domain, is required for tubulin binding. We provide evidence that FKBP52 prevents tubulin polymerization and that an 84 residue sequence located in the C-terminal part of the molecule (aa 375-458) is necessary and sufficient for its microtubule depolymerization activity. In colocalization experiments in PC12 cells, FKBP52 is associated with tubulin in motile cellular compartments. Furthermore, we suggest that, by using siRNA, a decrease of FKBP52 expression in PC12 cells may lead to differentiated cell phenotype characterized by neurite extensions. Collectively, our data define an unexpected property of FKBP52 as a novel regulator of microtubule dynamics. The possible role of microtubule formation and tubulin binding of other immunophilins such as FKBP12 and FKBP51 is discussed

Direct Crosstalk Between O-GlcNAcylation and Phosphorylation of Tau Protein Investigated by NMR Spectroscopy

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Neuronal Ndrg4 Is Essential for Nodes of Ranvier Organization in Zebrafish

International audienceAxon ensheathment by specialized glial cells is an important process for fast propagation of action potentials. The rapid electrical conduction along myelinated axons is mainly due to its saltatory nature characterized by the accumulation of ion channels at the nodes of Ranvier. However, how these ion channels are transported and anchored along axons is not fully understood. We have identified N-myc downstream-regulated gene 4, ndrg4, as a novel factor that regulates sodium channel clustering in zebrafish. Analysis of chimeric larvae indicates that ndrg4 functions autonomously within neurons for sodium channel clustering at the nodes. Molecular analysis of ndrg4 mutants shows that expression of snap25 and nsf are sharply decreased, revealing a role of ndrg4 in controlling vesicle exocytosis. This uncovers a previously unknown function of ndrg4 in regulating vesicle docking and nodes of Ranvier organization, at least through its ability to finely tune the expression of the t-SNARE/NSF machinery

The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior.

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The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior

The KAES methodology for efficient evaluation of dependability-related properties is proposed. KAES targets systems representable by Stochastic Petri Nets-based models, composed by a large number of submodels where interconnections are managed through synchronization at action level. The core of KAES is a new numerical solution of the underlying CTMC process, based on powerful mathematical techniques, including Kronecker algebra, Tensor Trains and Exponential Sums. Specifically, advancing on existing literature, KAES addresses efficient evaluation of the Mean-Time-To-Absorption in CTMC with absorbing states, exploiting the basic idea to further pursue the symbolic representation of the elements involved in the evaluation process, so to better cope with the problem of state explosion. As a result, computation efficiency is improved, especially when the submodels are loosely interconnected and have small number of states. An instrumental case study is adopted, to show the feasibility of KAES, in particular from memory consumption point of view

Tetanus toxin injection does not impair sodium channel clustering and myelination in the PNS.

<p>(A) Lateral view of a control foxd3::GFP embryo at 3 dpf. Arrows indicate SCs along the PLLn. (A’) Acetylated tubulin expression in the same control embryo at 3 dpf. Arrows show the PLLn axons. (A”) Merge of (A) and (A’). (C) Lateral view of a <i>TeNT</i> injected foxd3::GFP embryo at 3 dpf. Arrows indicate SCs along the PLLn. (C’) Acetylated tubulin expression in the same <i>TeNT</i> injected embryo at 3 dpf. Arrows indicate the PLLn axons. (C”) Merge of (C) and (C’). Scale bars = 50μm. Sodium channel labeling in control (B) and <i>TeNT</i> injected embryo (D) and their corresponding axons of the PLLn, (B’) and (D’) respectively. (B”) merge of (B) and (B’), (D”) merge of (D) and (D’). Scale bars = 10μm. (E,F) Transmission electron micrographs showing cross-section through (E) control and (F) <i>TeNT</i> injected embryos’ PLLn at 4 dpf. (E) Control PLLn shows an average of 6 myelinated axons (blue asterisks). (F) An average of 6 myelinated axons (blue asterisks) is also observed in the <i>TeNT</i> injected embryo’s PLLn. (S: Schwann cell). Scale bars = 0.5μm. (J) Quantification of the number of nodes seen in the PLLn shows no significant difference between controls and <i>TeNT</i> injected embryos.</p