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PubMed2000

FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2.

Apoptosis induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO-2L) has been shown to exert important functions during various immunological processes. The involvement of the death adaptor proteins FADD/MORT1, TRADD, and RIP and the apoptosis-initiating caspases-8 and -10 in death signaling by the two death-inducing TRAIL receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are controversial. Analysis of the native TRAIL death-inducing signaling complex (DISC) revealed ligand-dependent recruitment of FADD/MORT1 and caspase-8. Differential precipitation of ligand-stimulated TRAIL receptors demonstrated that FADD/MORT1 and caspase-8 were recruited to TRAIL-R1 and TRAIL-R2 independently of each other. FADD/MORT1- and caspase-8-deficient Jurkat cells expressing only TRAIL-R2 were resistant to TRAIL-induced apoptosis. Thus, FADD/MORT1 and caspase-8 are essential for apoptosis induction via TRAIL-R2.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Physical and functional interactions between Daxx and DNA methyltransferase 1-associated protein, DMAP1.

Daxx has been shown to play an essential role in type I IFN-alphabeta-mediated suppression of B cell development and apoptosis. Recently, we demonstrated that Tyk2 is directly involved in IFN signaling for the induction and translocation of Daxx, which may result in growth arrest and/or apoptosis of B lymphocyte progenitors. To clarify how Daxx regulates B cell development, we examined Daxx interacting partners by yeast two-hybrid screening. DNA methyltransferase 1 (DNMT1)-associated protein (DMAP1) was identified and demonstrated to interact with Daxx. The interaction regions in both proteins were mapped, and the cellular localization of the interaction was examined. Both Daxx and DMAP1 formed a complex with DNMT1 and colocalized in the nucleus. DMAP1 enhanced Daxx-mediated repression of glucocorticoid receptor transcriptional activity. Furthermore, Daxx protected protein degradation of DMAP1 in vivo. These results provide the novel molecular link between Daxx and DNMT1, which establishes a repressive transcription complex in the nucleus.

Adaptor Proteins, Signal Transducing↗
PubMed1998

The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins.

Nuclear import and export of viral nucleic acids is crucial for the replication cycle of many viruses, and elucidation of the mechanism of these steps may provide a paradigm for understanding general biological processes. Influenza virus replicates its RNA genome in the nucleus of infected cells. The influenza virus NS2 protein, which had no previously assigned function, was shown to mediate the nuclear export of virion RNAs by acting as an adaptor between viral ribonucleoprotein complexes and the nuclear export machinery of the cell. A functional domain on the NS2 with characteristics of a nuclear export signal was mapped: it interacts with cellular nucleoporins, can functionally replace the effector domain of the human immunodeficiency virus type 1 (HIV-1) Rev protein and mediates rapid nuclear export when cross-linked to a reporter protein. Microinjection of anti-NS2 antibodies into infected cells inhibited nuclear export of viral ribonucleoproteins, suggesting that the Rev-like NS2 mediates this process. Therefore, we have renamed this Rev-like factor the influenza virus nuclear export protein or NEP. We propose a model by which NEP acts as a protein adaptor molecule bridging viral ribonucleoproteins and the nuclear pore complex.

Amino Acid Sequence↗
PubMedDate not supplied

Crossing over analysis at pachytene in man.

The distribution of anti-MLH1 (MutL homologue 1) antibody labelling was studied in human prophase meiocytes. A labelling pattern consisting of distinct foci, always associated with the synaptonemal complex (SC) and never in closely juxtaposed pairs, was observed. Comparison of the number and general positions of autosomal foci with previous studies of the number and positions of autosomal chiasmata indicates that the anti-MLH1 antibody marks sites of crossing over in human pachytene spermatocytes. A mean number of 50.9 autosomal foci was observed from 46 human pachytene spermatocytes corresponding to a genetic length of 2545 cm. Division of these spermatocytes into sub-stages revealed that the number of foci remains stable throughout pachytene. A focus was found on the XY bivalent in 56.5% of the nuclei. The presence or absence of foci from the XY bivalent could not be correlated to pachytene sub-stage.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Hrs, a mammalian master molecule in vesicular transport and protein sorting, suppresses the degradation of ESCRT proteins signal transducing adaptor molecule 1 and 2.

The degradation and sorting of cytoplasmic and cell-surface proteins are crucial steps in the control of cellular functions. We previously identified three mammalian Vps (vacuolar protein sorting) proteins, Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and signal transducing adaptor molecule (STAM) 1 and -2, which are tyrosine-phosphorylated upon cytokine/growth factor stimulation. Hrs and the STAMs each contain a ubiquitin-interacting motif and through formation of a complex are involved in the vesicle transport of early endosomes. To explore the mechanism and cellular function of this complex in mammalian cells, we established an Hrs-defective fibroblastoid cell line (hrs(-/-)); embryos with this genotype died in utero. In the hrs(-/-) cells only trace amounts of STAM1 and STAM2 were detected. Introduction of wild-type Hrs or an Hrs mutant with an intact STAM binding domain (Hrs-dFYVE) fully restored STAM1 and STAM2 expression, whereas mutants with no STAM binding ability (Hrs-dC2, Hrs-dM) failed to express the STAMs. This regulated control of STAM expression by Hrs was independent of transcription. Interestingly, STAM1 degradation was mediated by proteasomes and was partially dependent on the ubiquitin-interacting motif of STAM1. Revertant Hrs expression in hrs(-/-) cells not only led to the accumulation of ubiquitinated proteins, including intracytoplasmic vesicles, but also restored STAM1 levels in early endosomes and eliminated the enlarged endosome phenotype caused by the absence of Hrs. These results suggest that Hrs is a master molecule that controls in part the degradation of STAM1 and the accumulation of ubiquitinated proteins.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Homer-PIKE complex: a novel link between mGluRI and PI 3-kinase.

Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, are thought to signal through the phospholipase and inositol (1,4,5)-trisphosphate receptor system, or through the adenylyl cyclase and protein kinase C system. Rong et al. have recently identified a new phosphoinositide (PI) 3-kinase enhancer (PIKE-L) that links group I mGlu receptors (mGluRI) to PI 3-kinase through Homer proteins, adaptors that bind mGluRI. mGluRI agonists enhanced mGluRI-Homer-PIKE-L complex formation, leading to activation of PI 3-kinase and inhibition of staurosporine-induced neuronal apoptosis. These results reveal a novel anti-apoptotic signaling mechanism that involves formation of an mGluRI signaling complex.

Animals↗
PubMed2006

Molecular interaction of NADPH oxidase 1 with betaPix and Nox Organizer 1.

It is well established that growth-factor-induced reactive oxygen species (ROS) act as second messengers in cell signaling. We have previously reported that betaPix, a guanine nucleotide exchange factor for Rac, interacts with NADPH oxidase 1 (Nox1) leading to EGF-induced ROS generation. Here, we report the identification of the domains of Nox1 and betaPix responsible for the interaction between the two proteins. GST pull-down assays show that the PH domain of betaPix binds to the FAD-binding region of Nox1. We also show that overexpression of the PH domain of betaPix results in inhibition of superoxide anion generation in response to EGF. Additionally, NADPH oxidase Organizer 1 (NoxO1) is shown to interact with the NADPH-binding region of Nox1. These results suggest that the formation of the complex consisting of Nox1, betaPix, and NoxO1 is likely to be a critical step in EGF-induced ROS generation.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Apoptotic cell death and amyloid precursor protein signaling in neuroblastoma SH-SY5Y cells.

We have recently shown that the amyloid precursor protein (APP) and a subset of its C-terminal fragments (CTFs) are tyrosine phosphorylated in human brain and in cultured cells. Tyrosine phosphorylation generates a substrate that is sequentially bound by the adaptor proteins ShcA and Grb2, and this interaction is significantly enhanced in Alzheimer's disease brains. Here we have studied the APP/CTFs phosphorylation and ShcA activation in a human neuroblastoma cell line, SH-SY5Y, under basal and apoptotic conditions. To commit these cells to apoptosis, we used staurosporin, a well-known apoptotic inducer and protein kinase C blocker. Our data suggest the following: (1) in normally proliferating SH-SY5Y cells, full-length APP is complexed with Grb2[Q3], likely through its SH2 domain; (2) upon induction of apoptosis, APP is degraded and ShcA-Grb2 coimmunoprecipitates with CTFs recognized by anti-APP antibodies; and (3) caspase inhibitors partially block the degradation of APP and the coprecipitation of CTFs with ShcA-Grb2 adaptors. In summary, our data suggest that in SH-SY5Y cells, tyrosine-phosphorylated APP is involved in a complex with ShcA-Grb2 adaptors that is disrupted during apoptosis. The abnormal degradation of APP and consequent increased levels of CTFs (as has been observed in Alzheimer's disease and Down's syndrome) generate a complex between tyrosine-phosphorylated CTFs and intracellular adaptors. The signaling through APP and its CTFs may have significant relevance for apoptotic cell death in Alzheimer's disease.

Alzheimer Disease↗
PubMed2004

Mouse RanBPM is a partner gene to a germline specific RNA helicase, mouse vasa homolog protein.

Germ cell-specific ATP-dependent RNA helicase, the product of the mouse vasa homolog (Mvh), has been shown to play an essential role in the development of the male germ cell. In male Mvh knockout mice, premeiotic germ cells arrest at the zygotene stage. To investigate the role of MVH protein in the progression of meiosis, we searched for genes encoding partners that interact with MVH in testicular germ cells. Using the yeast two-hybrid system, we found that MVH interacts with mouse RanBPM, a Ran-GTP binding protein involved in microtubule nucleation. RanBPM is predominantly expressed in the testis, especially in maturating spermatocytes. Within the cell, RanBPM and MVH are closely associated with perinuclear RNA-protein complexes and chromatoid bodies. The interaction of MVH with RanBPM points to a functional relationship between translational regulation and the microtubule nucleation during meiosis. Mol. Reprod. Dev. 66: 1-7, 2004.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Integrin tyrosine phosphorylation in platelet signaling.

The beta 3 integrin cytoplasmic tyrosine (ICY) motif of alpha IIb beta 3 becomes tyrosine phosphorylated during platelet aggregation, causing Shc and myosin to interact with the beta-integrin cytoplasmic domain. Platelets from mice lacking beta 3 ICY motif tyrosines formed defective aggregates and poorly retracted clots, establishing integrin tyrosine phosphorylation as a key mediator of beta 3-integrin signals.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Agonist-stimulated beta-adrenergic receptor internalization requires dynamic cytoskeletal actin turnover.

Stimulation of beta-adrenergic receptors (betaARs) leads to sequential recruitment of beta-arrestin, AP-2 adaptor protein, clathrin, and dynamin to the receptor complex, resulting in endocytosis. Whether a dynamic actin cytoskeleton is required for betaAR endocytosis is not known. In this study, we have used beta(1)- and beta(2) ARs, two ubiquitously expressed members of the betaAR family, to comprehensively evaluate the requirement of the actin cytoskeleton in receptor internalization. The integrity of the actin cytoskeleton was manipulated with the agent latrunculin B (LB) and mutants of cofilin to depolymerize actin filaments. Treatment of cells with LB resulted in dose-dependent depolymerization of the cortical actin cytoskeleton that was associated with significant attenuation in internalization of beta(2)ARs, beta(1)ARs, and mutants of beta(1)ARs that internalize via either clathrin- or caveolin-dependent pathways. Importantly, LB treatment did not inhibit beta-arrestin translocation or dynamin recruitment to the agonist-stimulated receptor. To unequivocally demonstrate the requirement of the actin cytoskeleton for beta(2)AR endocytosis, we used an actin-binding protein cofilin that biochemically depolymerizes and severs actin filaments. Isoproterenol-mediated internalization of beta(2)AR was completely blocked in the presence of wild type cofilin, which could be rescued by a mutant of cofilin that mimics a constitutive phosphorylated state and leads to normal agonist-stimulated beta(2)AR endocytosis. Finally, treatment with jasplakinolide, an inhibitor of actin turnover, resulted in dose-dependent inhibition of beta(2)AR internalization, suggesting that turnover of actin filaments at the receptor complex is required for endocytosis. Taken together, these data demonstrate that intact and functional dynamic actin cytoskeleton is required for normal betaAR internalization.

Actin Cytoskeleton↗
PubMed2003

The yeasts Rho1p and Pkc1p regulate the transport of chitin synthase III (Chs3p) from internal stores to the plasma membrane.

During cell stress, Saccharomyces cerevisiae increases the synthesis of chitin and glucans to strengthen and repair the cell wall. In this study, we show that under conditions of cell stress, the steady-state localization of chitin synthase III (Chs3p) shifts from internal stores (chitosomes) to the plasma membrane (PM). This redistribution occurs rapidly and requires the activators of the cell wall stress response signaling pathway, the G protein Rho1p, and the protein kinase Pkc1p, but not the cell integrity response mitogen-activated protein kinase cascade. Furthermore, expression of activated forms of Rho1p or Pkc1p, in the absence of cell stress, is sufficient to redistribute Chs3p to the PM. In cells deficient for both the clathrin adaptor complex 1 and Chs6p, where Chs3p is transported to the PM by an alternative bypass pathway, cell wall stress did not cause mobilization of Chs3p, suggesting that Rho1p/Pkc1p regulate Chs3p exit from the trans-Golgi network. The mobilization of an intracellular reservoir of Chs3p presents a novel opportunity to investigate the genetic basis of regulated vesicular traffic.

Cell Membrane↗
PubMed1997

Suppressors of YCK-encoded yeast casein kinase 1 deficiency define the four subunits of a novel clathrin AP-like complex.

In Saccharomyces cerevisiae, the redundant YCK1 and YCK2 genes (Yeast Casein Kinase 1) are required for viability. We describe here the molecular analysis of four mutations that eliminate the requirement for Yck activity. These mutations alter proteins that resemble the four subunits of clathrin adaptors (APs), with highest sequence similarity to those of the recently identified AP-3 complex. The four yeast subunits are associated in a high-molecular-weight complex. These proteins have no essential function and are not redundant for function with other yeast AP-related proteins. Combination of suppressor mutations with a clathrin heavy chain mutation (chc1-ts) confers no synthetic growth defects. However, a yck(ts) mutation shows a strong synthetic growth defect with chc1-ts. Moreover, endocytosis of Ste3p is dramatically decreased in yck(ts) cells and is partially restored by the AP suppressor mutations. These results suggest that vesicle trafficking at the plasma membrane requires the activity of Yck protein kinases, and that the new AP-related complex may participate in this process.

Adaptor Proteins, Vesicular Transport↗
PubMed2007

Tyrosine kinase Syk associates with toll-like receptor 4 and regulates signaling in human monocytic cells.

Toll-like receptor 4 (TLR4) induces an innate immune response in mammals by recognizing lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria. In this study, we show that tyrosine kinase Syk constitutively associates with TLR4 in THP-1 cells. As previously reported in peripheral blood mononuclear cells, TLR4 gets inducibly tyrosine phosphorylated upon LPS engagement in THP-1 cells. Piceatannol, a pharmacological inhibitor of the tyrosine kinase Syk, abrogates TLR4 tyrosine phosphorylation at low doses. The kinetics of TLR4 tyrosine phosphorylation in THP-1 cells coincides with an early wave of Syk tyrosine phosphorylation. Additionally, serine threonine kinase interleukin-1 (IL1) receptor-associated kinase 1 (IRAK-1) is transiently recruited to the complex containing adaptor molecule MyD88, TLR4 and Syk within 1 min of LPS engagement and dissociates by 30 min. Finally, the inhibition of Syk with piceatannol has no effect on LPS-mediated release of cytokines IL6, IL1beta, tumor necrosis factor-alpha, neither on chemokines macrophage inhibitory protein (MIP)1alpha, MIP1beta, monocyte chemoattractant protein -1, IL8, Groalpha and RANTES. However, IL10 and IL12p40 releases are significantly inhibited. Our findings implicate Syk as a novel modulator of LPS-mediated TLR4 responses in human monocytic cells and shed insight into the kinetics of early complex formation upon LPS engagement.

Cell Line, Tumor↗
PubMed1994

A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family.

Signaling by tyrosine kinase receptors is mediated by selective interactions between individual Src homology 2 (SH2) domains of cytoplasmic effectors and specific phosphotyrosine residues in the activated receptor. Here, we report the existence in the hepatocyte growth factor/scatter factor (HGF/SF) receptor of a multifunctional docking site made of the tandemly arranged degenerate sequence YVH/NV. Phosphorylation of this site mediates intermediate- to high-affinity interactions with multiple SH2-containing signal transducers, including phosphatidylinositol 3-kinase, phospholipase C gamma, pp60c-src, and the GRB-2-Sos complex. Mutation of the two tyrosines results in loss of biological function, as shown by abrogation of the transforming activity in the oncogenic counterpart of the receptor. The same bidentate motif is conserved in the evolutionarily related receptors Sea and Ron, suggesting that in all members of the HGF/SF receptor family, signal transduction is channeled through a multifunctional binding site.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Activation of Raf-mitogen-activated protein kinase signaling pathway by 1,25-dihydroxyvitamin D3 in normal human keratinocytes.

The biologic effects of the vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are believed to be mediated by an intracellular vitamin D receptor, which after ligand binding acts as a transcription factor modulating expression of a variety of genes. Besides having a well-known role in calcium metabolism, this hormone is an important regulator of proliferation in a majority of normal and neoplastic cells. Keratinocytes provide a convenient model for investigating the growth-related effects of vitamin D in normal cells. Growth of keratinocytes may be either stimulated or inhibited by 1,25(OH)2D3, depending on the degree of cell differentiation. We show here that 1,25(OH)2D3 stimulates DNA synthesis via sequential activation of Raf and the mitogen-activated protein kinase. Activation of these kinases is independent on protein and mRNA synthesis and is preceded by rapid tyrosine phosphorylation of an adaptor protein p66 (Shc) and formation of a complex between p66 Shc, a bridging molecule Grb2, and a Ras activator, mSos. Vitamin D receptor protein associates with Shc, indicating that this steroid hormone is able to signal through the transcription-independent pathways similar to those used by peptide hormones and cytokines.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Platelet adhesion signalling and the regulation of thrombus formation.

Platelets perform a central role in haemostasis and thrombosis. They adhere to subendothelial collagens exposed at sites of blood vessel injury via the glycoprotein (GP) Ib-V-IX receptor complex, GPVI and integrin alpha(2)beta(1). These receptors perform distinct functions in the regulation of cell signalling involving non-receptor tyrosine kinases (e.g. Src, Fyn, Lyn, Syk and Btk), adaptor proteins, phospholipase C and lipid kinases such as phosphoinositide 3-kinase. They are also coupled to an increase in cytosolic calcium levels and protein kinase C activation, leading to the secretion of paracrine/autocrine platelet factors and an increase in integrin receptor affinities. Through the binding of plasma fibrinogen and von Willebrand Factor to integrin alpha(IIb)beta(3), a platelet thrombus is formed. Although increasing evidence indicates that each of the adhesion receptors GPIb-V-IX and GPVI and integrins alpha(2)beta(1) and alpha(IIb)beta(3) contribute to the signalling that regulates this process, the individual roles of each are only beginning to be dissected. By contrast, adhesion receptor signalling through platelet endothelial cell adhesion molecule 1 (PECAM-1) is implicated in the inhibition of platelet function and thrombus formation in the healthy circulation. Recent studies indicate that understanding of platelet adhesion signalling mechanisms might enable the development of new strategies to treat and prevent thrombosis.

Blood Platelets↗
PubMed1989

Cloning of cDNAs encoding two related 100-kD coated vesicle proteins (alpha-adaptins).

Coat proteins of approximately 100-kD (adaptins) are components of the adaptor complexes which link clathrin to receptors in coated vesicles. The alpha-adaptins, which are found exclusively in endocytic coated vesicles, separate into two bands on SDS gels, designated A and C (Robinson, M. S., 1987. J. Cell Biol. 104:887-895). Two distinct cDNAs (sequences 1 and 2) encoding the two alpha-adaptins were cloned from a mouse brain cDNA library. Southern blotting indicates that there is one copy of each of the two alpha-adaptin genes, and that there are no additional closely related genes. Based on the size of the predicted protein products of the two genes (108 and 104 kD), the relative abundance of the two messages in brain and liver, and the reactivity of a sequence 1 fusion protein with different antibodies, it was possible to conclude that sequence 1 codes for A and sequence 2 for C. The two protein sequences are strikingly homologous to each other (84% identical amino acids), the major difference being an additional stretch of 41 amino acids, rich in prolines and acidic residues, inserted into the COOH-terminal half of A. In situ hybridization carried out on mouse brain sections indicates that the same cell type may express both transcripts, but that their relative expressions vary. Antipeptide antibodies are now being raised to find out whether the proteins are localized in functionally distinct populations of endocytic coated vesicles.

Adaptor Protein Complex alpha Subunits↗