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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function of the clock, inhibition of this process has not yet been shown to alter mammalian circadian rhythm. We have developed a cell-based model of PER2 degradation. Murine PER2 (mPER2) hyperphosphorylation induced by the cell-permeable protein phosphatase inhibitor calyculin A is rapidly followed by ubiquitination and degradation by the 26S proteasome. Proteasome-mediated degradation is critically important in the circadian clock, as proteasome inhibitors cause a significant lengthening of the circadian period in Rat-1 cells. CKIepsilon (casein kinase Iepsilon) has been postulated to prime PER2 for degradation. Supporting this idea, CKIepsilon inhibition also causes a significant lengthening of circadian period in synchronized Rat-1 cells. CKIepsilon inhibition also slows the degradation of PER2 in cells. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. Cell culture-based biochemical assays combined with measurement of cell-based rhythm complement genetic studies to elucidate basic mechanisms controlling the mammalian clock.
Mol Cell Biol 2005 Apr
PMID:Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. 1576 83

Herpes simplex virus 1 (HSV-1) enters cells via initial binding of envelope glycoproteins (g) C and B to cell-surface glycosaminoglycans (GAGs) and subsequent membrane fusion involving envelope gD, gB, and gH/gL. Current insights suggest that the fusion process is initiated by interaction of gD with a cognate cellular receptor, such as the widely distributed cell adhesion molecule nectin-1. To redirect the tropism of HSV-1, we have generated a soluble adapter protein (P-V528LH) comprising the gD-binding variable domain of nectin-1 fused to a single-chain antibody (528LH) recognizing the EGF receptor. The adapter molecule enabled HSV-1 entry into naturally nonpermissive CHO cells expressing the human EGF receptor, but not into CHO cells lacking the receptor, and entry was not observed when the antibody portion of the adapter was replaced with an antibody of different specificity. Adapter-mediated entry increased with the viral dose and was nearly as efficient as direct viral entry into nectin-1-bearing CHO cells. Entry depended on viral gD and was diminished in the absence of cellular GAGs. These experiments represent the first demonstration that a soluble molecule can direct HSV infection via a new receptor, supporting the possible utility of this approach for HSV retargeting.
Mol Ther 2005 Apr
PMID:Herpes simplex virus targeting to the EGF receptor by a gD-specific soluble bridging molecule. 1577 64

The lung is continuously exposed to bacteria and their products, and has developed a complex defense mechanism, including neutrophil recruitment. In mice, keratinocyte cell-derived chemokine and macrophage inflammatory protein-2 are the major chemokines for neutrophil recruitment into the lung. We have previously described a role for C-X-C chemokine (CXCL5) in neutrophil trafficking during lipopolysaccharide (LPS)-induced lung inflammation in mice. The aims of the present study were to identify the cellular origin of CXCL5 and to determine the signaling cascades that regulate its expression in the lung during LPS-induced inflammation and in isolated LPS-stimulated CXCL5-expressing cells. Our immunohistochemical analysis indicates that alveolar epithelial type II (AEII) cells are the primary source of CXCL5 in the rodent lung. These in vivo observations were confirmed with primary AEII cells. In addition, our data indicate that the Toll-like receptor 4 (TLR4) signaling cascade involving TLR4, myeloid differentiation factor 88, and Toll-IL-1R domain-containing adapter protein is required to induce CXCL5 expression in the lung. Furthermore, p38 and c-Jun N-terminal kinases are involved in lung CXCL5 expression. Similarly, TLR4, and p38 and c-Jun N-terminal kinases, are associated with LPS-induced CXCL5 expression in AEII cells. These novel observations demonstrate that activation of AEII cells via TLR4-dependent signaling is important for the production of CXCL5 in the lung exposed to LPS.
Am J Respir Cell Mol Biol 2005 Jun
PMID:Induction of CXCL5 during inflammation in the rodent lung involves activation of alveolar epithelium. 1577 92

The voltage-gated sodium channel Na(v)1.8 produces a tetrodotoxin-resistant current and plays a key role in nociception. Annexin II/p11 binds to Na(v)1.8 and facilitates insertion of the channel within the cell membrane. However, the mechanisms responsible for removal of specific channels from the cell membrane have not been studied. We have identified a novel protein, clathrin-associated protein-1A (CAP-1A), which contains distinct domains that bind Na(v)1.8 and clathrin. CAP-1A is abundantly expressed in DRG neurons and colocalizes with Na(v)1.8 and can form a multiprotein complex with Na(v)1.8 and clathrin. Coexpression of CAP-1A and Na(v)1.8 in DRG neurons reduces Na(v)1.8 current density by approximately 50% without affecting the endogenous or recombinant tetrodotoxin-sensitive currents. This effect of CAP-1A is blocked by bafilomycin A1 treatment of transfected DRG neurons. CAP-1A thus is the first example of an adapter protein that links clathrin and a sodium channel and may regulate Na(v)1.8 channel density at the cell surface.
Mol Cell Neurosci 2005 Apr
PMID:CAP-1A is a novel linker that binds clathrin and the voltage-gated sodium channel Na(v)1.8. 1579 11

Adhesion and degranulation-promoting adapter protein (ADAP) is critically involved in downstream signalling events triggered by the activation of the T cell receptor. Cytokine production, proliferation and integrin clustering of T cells are dependent on ADAP function, but the molecular basis for these processes is poorly understood. We now show the hSH3 domain of ADAP to be a lipid-interaction module that binds to acidic lipids, including phosphatidylinositides. Positively charged surface patches of the domain preferentially bind to polyvalent acidic lipids such as PIP2 or PIP3 over the monovalent PS phospholipid and this interaction is dependent on the N-terminal helix of the hSH3 domain fold. Basic amino acid side-chains from the SH3 scaffold also contribute to lipid binding. In the context of T cell signalling, our findings suggest that ADAP, upon recruitment to the cell-cell junction as part of a multiprotein complex, directly interacts with phosphoinositide-enriched regions of the plasma membrane. Furthermore, the ADAP lipid interaction defines the helically extended SH3 scaffold as a novel member of membrane interaction domains.
J Mol Biol 2005 May 13
PMID:The helically extended SH3 domain of the T cell adaptor protein ADAP is a novel lipid interaction domain. 1584 31

MyD88 is an adapter protein required for the induction of proinflammatory cytokines by most Toll-like receptors (TLR), and Pseudomonas aeruginosa expresses ligands for multiple TLRs. MyD88(-/-) (KO) mice are highly susceptible to aerosolized P. aeruginosa, failing to elicit an early inflammatory response and permitting a 3-log increase in bacterial CFU in the lungs by 24 h after infection. We hypothesized that alveolar macrophages are the first cells to recognize and kill aerosolized P. aeruginosa in an MyD88-dependent fashion due to their location within the airways. To determine which cells in the lungs mediate MyD88-dependent defenses against P. aeruginosa, we generated radiation bone marrow (BM) chimeras between MyD88KO and wild-type (WT) mice. MyD88KO mice transplanted with MyD88KO BM (MyD88KO-->MyD88KO mice) displayed uncontrolled bacterial replication, whereas all other chimeras controlled the infection by 24 h. However, at 4 h, both MyD88KO-->MyD88KO and WT-->MyD88KO mice permitted intrapulmonary bacterial replication, whereas MyD88KO-->WT and WT-->WT mice did not, indicating that the source of BM had little impact on the early control of infection. Similarly, the genotype of the recipient rather than that of the BM donor determined early neutrophil recruitment to the lungs. Whereas intrapulmonary TNF-alpha and IL-1beta production were associated with WT BM, levels of the CXC chemokines MIP-2 and KC as well as GM-CSF were associated with recipient genotype. We conclude that lung parenchymal and BM-derived cells collaborate in the MyD88-dependent response to P. aeruginosa infection in the lungs in mice.
Am J Respir Cell Mol Biol 2005 Nov
PMID:An essential role for non-bone marrow-derived cells in control of Pseudomonas aeruginosa pneumonia. 1610 80

SIT is a transmembrane adapter protein that modulates signals emanating from the T-cell receptor (TCR). Here, we have used gene-targeted mice to assess the role of SIT for T-cell development and peripheral T-cell functions. SIT(-/-) double-positive thymocytes show an upregulation of the activation markers CD5 and CD69, suggesting that SIT negatively regulates TCR-mediated signals at the CD4(+) CD8(+) stage of thymic development. This assumption is further supported by the observation that in female H-Y TCR transgenic mice, positive selection is enhanced and even converted to negative selection. Similarly, mature peripheral T cells are hyperresponsive towards TCR-mediated stimuli and produce larger amounts of T-helper 1 (TH1) cytokines, and SIT-deficient mice show an increased susceptibility to develop experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. These results demonstrate that SIT is a critical negative regulator of TCR-mediated signaling and finely tunes the signals required for thymic selection and peripheral T-cell activation.
Mol Cell Biol 2005 Sep
PMID:The transmembrane adapter protein SIT regulates thymic development and peripheral T-cell functions. 1610 3

Fraser syndrome is a recessive multisystem disorder characterized by embryonic epidermal blistering, cryptophthalmos, syndactyly, renal defects and a range of other developmental abnormalities. More than 17 years ago, the family of four mapped mouse blebs mutants was proposed as models of this disorder, given their striking phenotypic overlaps. In the last few years, these loci have been cloned, uncovering a family of three large extracellular matrix proteins and an intracellular adapter protein which are required for normal epidermal adhesion early in development. The proteins have also been shown to play a crucial role in the development and homeostasis of the kidney. We review the cloning and characterization of these genes and explore the consequences of their loss.
Hum Mol Genet 2005 Oct 15
PMID:The genetics of Fraser syndrome and the blebs mouse mutants. 1624 25

Pulmonary accumulation of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IFP/UIP) has been linked to (1) increased migration of a circulating pool of fibrocytes, (2) cell proliferation, and (3) resistance to apoptosis. The mechanism of physiologic apoptosis of lung fibroblasts is poorly understood. Using normal and fibrotic human lung fibroblasts and the human lung fibroblast cell line, MRC-5, we examined the regulation of Fas-induced apoptosis by the proinflammatory cytokines TNF-alpha and IFN-gamma. Herein, we show that the basal resistance of lung fibroblasts and myofibroblasts to Fas-induced apoptosis is overcome by sensitization with TNF-alpha. IFN-gamma did not sensitize cells to Fas-induced apoptosis, but exhibited synergistic activity with TNF-alpha. Sensitization by TNF-alpha was observed in MRC-5 cells and in fibroblasts and myofibroblasts from normal and fibrotic human lung, suggesting that this represents a conserved mechanism to engage Fas-induced apoptosis. The mechanism of sensitization was localized at the level of recruitment of the adapter protein, FADD, to the cytoplasmic domain of Fas. Collectively, these findings suggest that fibroblast apoptosis involves two steps, sensitization and induction, and that inadequate pulmonary inflammation in IPF/UIP may favor fibroblast accumulation by reducing sensitization to apoptosis.
Am J Respir Cell Mol Biol 2006 Mar
PMID:TNF-alpha sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis. 1627 60

Gaps remain in our understanding of the precise molecular mechanisms by which insulin regulates glucose uptake in fat and muscle cells. Recent evidence suggests that insulin action involves multiple pathways, each compartmentalized in discrete domains. Upon activation, the receptor catalyzes the tyrosine phosphorylation of a number of substrates. One family of these, the insulin receptor substrate (IRS) proteins, initiates activation of the phosphatidylinositol 3-kinase pathway, resulting in stimulation of protein kinases such as Akt and atypical protein kinase C. The receptor also phosphorylates the adapter protein APS, resulting in the activation of the G protein TC10, which resides in lipid rafts. TC10 can influence a number of cellular processes, including changes in the actin cytoskeleton, recruitment of effectors such as the adapter protein CIP4, and assembly of the exocyst complex. These pathways converge to control the recycling of the facilitative glucose transporter Glut4.
Mol Med
PMID:Insulin signaling and the regulation of glucose transport. 1630 72


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