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Results for “Adaptor Protein Complex 1”

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PubMed2001

STAM/EAST/Hbp adapter proteins--integrators of signalling pathways.

STAM/EAST/Hbp family of proteins consists of eight members well conserved from yeast to mammals. The basic domain architecture is comprised of an N-terminal Vps27, Hrs and STAM homology domain, a ubiquitin-interacting motif and a central Src homology-3 domain. Vertebrate members also carry an immunoreceptor tyrosine-based activation motif. STAM/EAST/Hbp proteins become tyrosine-phosphorylated by a variety of cytokines and growth factors. STAM 1 and STAM 2A are involved in cytokine-mediated signalling for DNA synthesis and c-myc induction. EAST and STAM 2A/Hbp play a role in receptor-mediated endo- and exocytosis and probably also in the regulation of actin cytoskeleton. Knockout experiments implicate a role for STAM 1 in neural cell survival. A picture is emerging of STAM/EAST/Hbp proteins acting as integrators of thus far mechanistically disparate cellular signalling events.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Functional organization of repeat addition processivity and DNA synthesis determinants in the human telomerase multimer.

Human telomerase is a multimer containing two human telomerase RNAs (hTRs) and most likely two human telomerase reverse transcriptases (hTERTs). Telomerase synthesizes multiple telomeric repeats using a unique repeat addition form of processivity. We investigated hTR and hTERT sequences that were essential for DNA synthesis and processivity using a direct primer extension telomerase assay. We found that hTERT consists of two physically separable functional domains, a polymerase domain containing RNA interaction domain 2 (RID2), reverse transcriptase (RT), and C-terminal sequences, and a major accessory domain, RNA interaction domain 1 (RID1). RID2 mutants defective in high-affinity hTR interactions and an RT catalytic mutant exhibited comparable DNA synthesis defects. The RID2-interacting hTR P6.1 helix was also essential for DNA synthesis. RID1 interacted with the hTR pseudoknot-template domain and hTERT's RT motifs and putative thumb and was essential for processivity, but not DNA synthesis. The hTR pseudoknot was essential for processivity, but not DNA synthesis, and processivity was reduced or abolished in dimerization-defective pseudoknot mutants. trans-acting hTERTs and hTRs complemented the processivity defects of RID1 and pseudoknot mutants, respectively. These data provide novel insight into the catalytic organization of the human telomerase complex and suggest that repeat addition processivity is one of the major catalytic properties conferred by telomerase multimerization.

Adaptor Proteins, Signal Transducing↗

PubMed2006

MNB/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins.

MNB/DYRK1A is a proline-directed serine/threonine kinase implicated in Down syndrome (DS). In an earlier screening, two proteins from adult rat brain, one 100kDa and the other 140 kDa, were found to be prominently phosphorylated by the kinase. The 100-kDa protein was previously characterized as an isoform of dynamin 1. In this study, we identified the 140-kDa protein as synaptojanin 1 (SJ1). MNB/DYRK1A phosphorylates SJ1 at multiple sites and produces complex behaviors in binding to amphiphysin 1 and intersectin 1 (ITSN1). However, the phosphorylation has little effect on the phosphatidylinositol phosphatase activity of SJ1. These results suggest that MNB/DYRK1A is involved in regulating the recruitment activity but not the phosphatase activity of SJ1. Our findings may be especially important in the etiology of DS because MNB/DYRK1A, SJ1, and ITSN1 are all located at or near the region of human chromosome 21, which is postulated to be involved in the disease.

Adaptor Proteins, Vesicular Transport↗

PubMed2006

Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain.

Embryonic multipotent neural precursors are exposed to extracellular signals instructing them to adopt different fates, neuronal or glial. However, the mechanisms by which precursors integrate these signals to make timely fate choices remained undefined. Here we show that direct nuclear signaling by a receptor tyrosine kinase inhibits the responses of precursors to astrocyte differentiation factors while maintaining their neurogenic potential. Upon neuregulin-induced activation and presenilin-dependent cleavage of ErbB4, the receptor's intracellular domain forms a complex with TAB2 and the corepressor N-CoR. This complex undergoes nuclear translocation and binds promoters of astrocytic genes, repressing their expression. Consistent with this observation, astrogenesis occurs precociously in ErbB4 knockout mice. Our studies define how presenilin-dependent nuclear signaling by a receptor tyrosine kinase directly regulates gene transcription and cell fate. This pathway could be of importance for neural stem cell biology and for understanding the pathogenesis of Alzheimer's disease.

Active Transport, Cell Nucleus↗

PubMed2000

Association of a duodenal follicular lymphoma and hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited predisposition to colorectal and endometrial cancers caused by germline mutation of mismatch repair genes, with hMLH1 and hMSH2 underlying the majority of the cases. Although lymphoid tumors are the most common tumors in mouse models for HNPCC, lymphomas are almost never encountered in patients who have HNPCC, except in rare families with germline homozygous deletion of hMLH1. We report the case of a 53-year-old man who had a history of colon cancers related to constitutional hMLH1 mutation and who was diagnosed as having a duodenal follicular lymphoma This diagnosis was supported by IgH-BCL2 rearrangement and BCL2 immunoreactivity in tumor cells. The association of both of these possibly related rare diseases has never been reported. To clarify this relationship, we searched for hMLH1 expression and mismatch repair deficiency in the duodenal lymphoma. hMLH1 immunostaining was positive in lymphoid tumor cells, and no microsatellite instability was detected. In agreement with mouse models for HNPCC, these results suggest the involvement of alternative mechanisms to complete mismatch repair deficiency for lymphomagenesis in HNPCC syndrome.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles.

BACKGROUND: Transcription factor Nrf2 regulates the expression of a set of detoxifying and anti-oxidant enzyme genes. Several lines of evidence suggest that electrophiles and reactive oxygen species liberate Nrf2 from its cytoplasmic repressor Keap1 and provoke the accumulation of Nrf2 in the nucleus. To elucidate the molecular mechanisms as to how Nrf2 is activated by inducers, we examined the cytoplasmic-nuclear shuttling and turnover of Nrf2. RESULTS: We found that Nrf2 is rapidly degraded through the proteasome pathway, while electrophiles cause Nrf2 nuclear translocation with concomitant stabilization. Crucial to the inducible accumulation of Nrf2 is the enfeebling of the Nrf2-Keap1 interaction by electrophiles. Exploiting mice which have the LacZ reporter gene knocked into the nrf2 locus, we revealed that the inducible accumulation of Nrf2 protein by electrophiles in macrophages and intestinal epithelia could be recapitulated by the Nrf2 N-terminal region in combination with a nuclear localization signal. We also found constitutive Nrf2 nuclear accumulation in Keap1-deficient mouse macrophages. CONCLUSIONS: Our results highlight the fact that Nrf2 protein turnover is regulated by Keap1 mediated subcellular compartmentalization.

Active Transport, Cell Nucleus↗

PubMed1999

The human high-affinity immunoglobulin G receptor activates SH2-containing inositol phosphatase (SHIP).

On cytokine-primed U937 cells, aggregation of the human high-affinity immunoglobulin receptor, FcgammaRI, initiates signal transduction cascades which lead to the release of calcium from intracellular stores and no significant calcium influx. In these cells, aggregation of FcgammaRI results in no significant increase in inositol trisphosphate production, but rather phospholipase D is activated. Here we show that, in interferon-gamma (IFN-gamma)-primed cells, the SH2 containing inositol 5' phosphatase, SHIP, is constitutively associated with the membrane fraction. Following aggregation of FcgammaRI, SHIP is rapidly and transiently tyrosine phosphorylated and becomes associated with the adapter molecule Shc. Shc also becomes tyrosine phosphorylated and translocates from the cytoplasm to the membrane fraction concomitant with the association between Shc and SHIP. Further, SHIP and Shc appear to be recruited to membrane-associated immune complexes following FcgammaRI aggregation. As no immunoreceptor inhibitory motif has been demonstrated to associate with FcgammaRI, these data suggest that SHIP may be recruited to the receptor through an SH2 domain interaction with Shc.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Isolation and characterization of a novel ligand-dependent thyroid hormone receptor-coactivating protein.

The thyroid hormone receptor (TR) regulates the expression of target genes upon binding to triiodothyronine (T3) response elements. In the presence of T3, the TR recruits coactivating proteins that both modulate and integrate the ligand response. We report here the cloning of a novel protein using the TR ligand-binding domain as bait in the yeast two-hybrid system. Analysis of a putative full-length clone demonstrates a cDNA sequence that encodes a protein of 920 amino acids with a size of 120 kDa (p120). Alignment with known sequences shows homology to a previously identified protein of unknown function, termed skeletal muscle abundant protein. Interaction studies demonstrate that p120 interacts with the TR AF-2 domain in the presence of ligand through a 111-amino acid region. Northern analysis demonstrates widespread expression in human tissues. Cotransfection assays in CV-1 cells demonstrate that p120 enhances TR-mediated transactivation on multiple T3 response elements in the presence of T3. In addition, CREB-binding protein synergizes with p120 to enhance this effect. When linked to the GAL4 DNA-binding domain, p120 is an activator of transcription alone. Thus, p120 satisfies a number of important criteria as a nuclear receptor coactivator.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1999

Expression of nuclear receptor interacting proteins TIF-1, SUG-1, receptor interacting protein 140, and corepressor SMRT in tamoxifen-resistant breast cancer.

Regulation of gene transcription as a consequence of steroid receptor-DNA interaction is mediated via nuclear receptor interacting proteins (RIPs), including coactivator or corepressor proteins, which interact with both the receptor and components of the basic transcriptional unit and vary between cell types. The aim of this study was to test the hypothesis that resistance of some breast carcinomas to tamoxifen was associated with inappropriate expression of some of these RIPs. Using Northern analysis, we observed no significant difference between the amount of either TIF-1 or SUG-1 mRNA expressed in parental MCF-7 and MCF-7 tamoxifen-resistant cell lines. However, the expression of RIP140 mRNA was lower in the resistant cell line and in the presence of estradiol, the level of RIP140 mRNA was higher in the resistant cells but not in the parental cells. In a cohort of 19 tamoxifen-resistant breast tumor samples, there was no significant difference in the level of the RIP140 and TIF-1 and corepressor SMRT mRNA compared with tamoxifen-treated tumors (n = 6) or untreated tumors (n = 21). However, SUG-1 mRNA was lower in resistant breast tumors. These data provide no support for increased expression of these RIPs or decreased expression of corepressor SMRT for being a mechanism for resistance of breast tumors to tamoxifen.

ATPases Associated with Diverse Cellular Activitie↗

PubMed1999

Mechanism of mitogenic effect of fluoride on fetal rat osteoblastic cells: evidence for Shc, Grb2 and P-CREB-dependent pathways.

Fluoride stimulates bone cell proliferation and nodule formation in fetal rat calvarial osteoblastic cells. In addition, fluoride enhances alkaline phosphatase activity, a marker of osteoblastic differentiation, in a dose-dependent manner. The effects of fluoroalumino complex (AlFx) on cell proliferation and differentiation were markedly reduced by tyrosine kinase inhibitor; 1 mM genistein or 1 microg/ml herbimycin. It suggests that tyrosine kinase-mediated mitogenic signaling involves a series of protein-protein interactions between tyrosine-phosphorylated receptors, Shc and Grb2, resulting in an AlFx-induced mitogenic effect. The results indicate that AlFx dose-dependently enhances the tyrosine phosphorylation of the adaptor molecule Shc (p52) and its association with Grb2 in the tyrosine kinase mediated pathway. In addition, AlFx decreases the phosphorylation level of CREB without any change on the amount of CREB protein. Taken together, the results suggest that adaptor proteins, including Shc and Grb2 of the protein tyrosine kinase cascade are implicated in fluoride-induced mitogenic activity of fetal rat calvarial osteoblastic cells. Furthermore, CREB which passes signals from cAMP to transcriptional factor CRE, modulates the fluoroaluminate-induced metabolism of bone cells via a decrease of phosphorylation level.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization.

Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) is a receptor, specific for MHC class I molecules, that inhibits lymphoid and myeloid cells. Here, we analyzed the molecular and cellular mechanisms by which ILT2 modulates T cell activation in primary CTLs and transfected T cell lines. We found that cross-linking with the TCR and the activity of Src tyrosine kinase p56(lck) were required for phosphorylation of ILT2 and subsequent recruitment of Src homology protein 1. In contrast, ILT2 triggering resulted in reduced phosphorylation of TCRzeta and linker for activation of T cells, which led to reduced TCRzeta-ZAP70 complex formation, as well as extracellular signal-related kinase 1 and 2 activation. Furthermore, ILT2 inhibited both superantigen and anti-TCR Ab-induced rearrangement of the actin cytoskeleton. The inhibitory effect mediated by ILT2 is probably concentrated at the APC-T cell interface because both TCR and ILT2 were strongly polarized toward the APC upon engagement by their specific ligands. Thus, ILT2 inhibits both signaling and cellular events involved in the activation of T cells.

Actins↗

PubMed1999

Role of protein kinase C in signal attenuation following T cell receptor engagement.

T lymphocyte activation through stimulation of the T cell receptor complex and co-stimulatory receptors is associated with acute tyrosine phosphorylation of intracellular proteins, which in turn mediate downstream signaling events that regulate interleukin-2 expression and cell proliferation. The extent of protein tyrosine phosphorylation is rapidly attenuated after only 1-2 min of stimulation as a means of tightly controlling the initial signaling response. Here we show that this attenuation of tyrosine phosphorylation of Shc, CrkL, and the proto-oncogene Cbl is mimicked by treatment of mouse T lymphocytes or cultured Jurkat cells with phorbol 12-myristate 13-acetate. This effect is blocked by the specific protein kinase C inhibitor GF109203X, but not by PD98059, an inhibitor of MEK1/2 kinase. Activation of protein kinase C by phorbol ester also causes rapid (t(1)/(2) = 2 min) dissociation of both CrkL and p85/phosphoinositide 3-kinase from Cbl concomitant with Cbl tyrosine dephosphorylation. More important, GF109203X treatment of Jurkat cells prior to T cell receptor stimulation by anti-CD3/CD4 antibodies results in an enhanced (2-fold) peak of Cbl phosphorylation compared with that observed in control cells. Furthermore, the rate of attenuation of both Cbl tyrosine phosphorylation and its association with CrkL following stimulation with anti-CD3/CD4 antibodies is much slower in Jurkat cells treated with GF109203X. Taken together, these data provide strong evidence that one or more isoforms of phorbol ester-responsive protein kinase C play a key role in a feedback mechanism that attenuates tyrosine phosphorylation of proteins and reverses formation of signaling complexes in response to T cell receptor activation.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Heat shock induces apoptosis independently of any known initiator caspase-activating complex.

Adaptive responses to mild heat shock are among the most widely conserved and studied in nature. More intense heat shock, however, induces apoptosis through mechanisms that remain largely unknown. Herein, we present evidence that heat shock activates an apical protease that stimulates mitochondrial outer membrane permeabilization and processing of the effector caspase-3 in a benzyloxycarbonyl-VAD-fluoromethyl ketone (polycaspase inhibitor)- and Bcl-2-inhibitable manner. Surprisingly, however, neither FADD.caspase-8 nor RAIDD.caspase-2 PIDDosome (p53-induced protein with a death domain) complexes were detected in dying cells, and neither of these initiator caspases nor the endoplasmic reticulum stress-activated caspases-4/12 were required for mitochondrial outer membrane permeabilization. Similarly, although cytochrome c was released from mitochondria following heat shock, functional Apaf-1.caspase-9 apoptosome complexes were not formed, and caspase-9 was not essential for the activation of caspase-3 or the induction of apoptosis. Thus, heat shock does not require any of the known initiator caspases or their activating complexes to promote apoptotic cell death but instead relies upon the activation of an apparently novel apical protease with caspase-like activity.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Importin beta-depending nuclear import pathways: role of the adapter proteins in the docking and releasing steps.

Nuclear imports of uridine-rich small nuclear ribonucleoprotein (U1 snRNP) and proteins with classical nuclear localization signal (cNLS-protein) are mediated by importin beta. However, due to the presence of different import signals, the adapter protein of the imported molecules and importin beta is different for each pathway. Although the adapter for cNLS-protein is importin alpha, the adapter for U1 snRNP is snurportin1 (SPN1). Herein, we show that the use of distinct adapters by importin beta results in differences at the docking and releasing step for these two import pathways. Nuclear pore complex (NPC) docking of U1 snRNP but not of cNLS-protein was inhibited by an anti-CAN/Nup214 antibody. Thus, the initial NPC-binding site is different for each pathway. Pull-down assays between immobilized SPN1 and two truncated forms of importin beta documented that SPN1 and importin alpha have different binding sites on importin beta. Importin beta fragment 1-618, which binds to SPN1 but not to importin alpha, was able to support the nuclear import of U1 snRNPs. After the translocation through the NPC, both import complexes associated with the nuclear side of the NPC. However, we found that the nature of the importin beta-binding domain of the adapters influences the release of the cargo into the nucleoplasm.

Active Transport, Cell Nucleus↗

PubMed2005

Subcellular targeting of oxidants during endothelial cell migration.

Endogenous oxidants participate in endothelial cell migration, suggesting that the enzymatic source of oxidants, like other proteins controlling cell migration, requires precise subcellular localization for spatial confinement of signaling effects. We found that the nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase adaptor p47(phox) and its binding partner TRAF4 were sequestered within nascent, focal complexlike structures in the lamellae of motile endothelial cells. TRAF4 directly associated with the focal contact scaffold Hic-5, and the knockdown of either protein, disruption of the complex, or oxidant scavenging blocked cell migration. An active mutant of TRAF4 activated the NADPH oxidase downstream of the Rho GTPases and p21-activated kinase 1 (PAK1) and oxidatively modified the focal contact phosphatase PTP-PEST. The oxidase also functioned upstream of Rac1 activation, suggesting its participation in a positive feedback loop. Active TRAF4 initiated robust membrane ruffling through Rac1, PAK1, and the oxidase, whereas the knockdown of PTP-PEST increased ruffling independent of oxidase activation. Our data suggest that TRAF4 specifies a molecular address within focal complexes that is targeted for oxidative modification during cell migration.

Cell Movement↗

PubMed1994

GRB2 and phospholipase C-gamma 1 associate with a 36- to 38-kilodalton phosphotyrosine protein after T-cell receptor stimulation.

GRB2, a 25-kDa protein comprising a single SH2 domain flanked by two SH3 domains, has been implicated in linking receptor protein tyrosine kinases (PTKs) to the Ras pathway by interacting with the guanine nucleotide exchange protein SOS. Previous studies have demonstrated that GRB2 directly interacts with Shc, a proto-oncogene product that is tyrosine phosphorylated upon receptor and nonreceptor PTK activation. In this report, we detected low levels of tyrosine phosphorylation of Shc and induced association with GRB2 upon T-cell receptor (TCR) stimulation. Instead, a prominent 36- to 38-kDa tyrosine phosphoprotein (pp36-38) associated with the SH2 domain of GRB2 and formed a stable complex with GRB2/SOS upon TCR stimulation. Cellular fractionation studies showed that whereas both GRB2 and SOS partitioned to the soluble and particulate fractions, pp36-38 was present exclusively in the particulate fraction. This phosphoprotein had the same apparent mobility in sodium dodecyl sulfate-polyacrylamide gel electrophoresis as the phosphoprotein that associates with phospholipase C-gamma 1 (PLC-gamma 1). Furthermore, following partial immunodepletion of GRB2 and of the associated pp36-38, there was a significant reduction in the amount of the 36-kDa phosphoprotein associated with PLC-gamma 1, suggesting that a trimeric PLC-gamma 1/pp36-38/GRB2 complex could form. In support of this notion, we have also been able to detect low levels of PLC-gamma 1 in GRB2 immunoprecipitates. We suggest that pp36-38 may be a bridging protein, coupling different signalling molecules to cytoplasmic PTKs regulated by the TCR.

Adaptor Proteins, Signal Transducing↗

PubMed2002

GIPC participates in G protein signaling downstream of insulin-like growth factor 1 receptor.

Several recent studies have demonstrated that insulin-like growth factor (IGF)-1-induced mitogen-activated protein kinase (MAP kinase) activation is abolished by pertussis toxin, suggesting that trimeric G proteins of the G(i) class are novel cellular targets of the IGF-1 signaling pathway. We report here that the intracellular domain of the Xenopus IGF-1 receptor is capable of binding to the Xenopus homolog of mammalian GIPC, a PDZ domain-containing protein previously identified as a binding partner of G(i)-specific GAP (RGS-GAIP). Binding of xGIPC to xIGF-1 receptor is independent of the kinase activity of the receptor and appears to require the PDZ domain of xGIPC. Injection of two C-terminal truncation mutants that retained the PDZ domain blocked IGF-1-induced Xenopus MAP kinase activation and oocyte maturation. While full-length xGIPC injection did not significantly alter insulin response, it greatly enhanced human RGS-GAIP in stimulating the insulin response in frog oocytes. This represents the first demonstration that GIPC x RGS-GAIP complex acts positively in IGF-1 receptor signal transduction.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2-mediated cell death but not gene induction.

Fas/Apo1 and other cytotoxic receptors of the tumor necrosis factor receptor (TNFR) family contain a cytoplasmic death domain (DD) [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] that activates the apoptotic process by interacting with the DD-containing adaptor proteins TNFR-associated DD protein (TRADD) [12] [13] and Fas-associated DD protein (FADD/MORT1) [14] [15], leading to the activation of cysteine proteases of the caspase family [16]. Stimulation of Fas/Apo1 leads to the formation of a receptor-bound death-inducing signaling complex (DISC), consisting of FADD and two different forms of caspase-8 [17] [18] [19]. Transient expression of a dominant-negative mutant of FADD impairs TNFR60-mediated and Fas/Apo1-mediated apoptosis [13] [20], but has no effect on TNF-related apoptosis-inducing ligand (TRAIL/Apo2L)-induced cell death [7] [8] [9] [10] [21]. To study the function of FADD in DD-receptor signaling in more detail, we established HeLa cells that stably expressed a green fluorescent protein (GFP)-tagged dominant-negative mutant of FADD, GFP-DeltaFADD. Interestingly, expression of this mutant inhibited cell death induced by TNFR60, Fas/Apo1 and TRAIL-R/Apo2. In addition, GFP-DeltaFADD did not interfere with TNF-mediated gene induction or with activation of NF-kappaB or Jun N-terminal kinase (JNK), demonstrating that FADD is part of the TNFR60-initiated apoptotic pathway but does not play a role in TNFR60-mediated gene induction. Fas/Apo1-mediated activation of JNK was unaffected by the expression of GFP-DeltaFADD, suggesting that in Fas/Apo1 signaling the apoptotic pathway and the activation of JNK diverge at a level proximal to the receptor, upstream of or parallel to FADD.

Adaptor Proteins, Signal Transducing↗