| |||
| |||
|
      |
|
 |
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| | | | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In brief: April 2002
Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites.
Experimentally based model of a complex between a snake toxin and the These two papers constitute significant progress in the elucidation of the extracellular domain of nicotinic acetylcholine receptors (nAChRs). The authors took advantage of the crystal structure of a molluscan acetylcholine-binding protein (AChBP), which shows substantial homology to nAChRs, and constructed three-dimensional models of the receptor. They identified key differences between AChBP and nAChRs in the binding pocket, and provided a structural basis for previous mutagenesis experiments. In the second paper, the authors model the
Induction of p57KIP2 expression by p73 The transcription factor p73 acts similarly to its homologue p53 in its ability to induce cell-cycle arrest and apoptosis. But, despite their ability to activate expression of many of the same genes, their functions are distinct — only p73 is involved in normal growth and development. Éva Bálint et al. now show that the p73
Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy.
Leukaemia cells release pro-inflammatory cytokines and pro-angiogenic factors in autocrine loops that promote leukaemic-cell growth and migration. A vascular endothelial growth factor family member, VEGFC, has similar effects: VEGFC treatment induces receptor phosphorylation, proliferation and increased survival in leukaemia cells in vitro. Moreover, VEGFC protected the cells against the apoptotic effects of three chemotherapeutic agents, so it might be involved in cancer drug resistance.
Role for CCR7 ligands in the emigration of newly generated T lymphocytes from neonatal thymus.
The developmental stages through which T cells pass in the thymus are well defined, but it is unclear what controls the emigration of T cells from the thymus. Previous studies have implicated chemokine signals in this process. By adding chemokines to fetal thymic organ cultures, and analysing thymic emigration in mice that are deficient or neutralized for certain chemokines and/or chemokine receptors, the authors highlight the importance of a CCL19- and CCR7-dependent pathway of thymic emigration.
Involvement of receptor-interacting protein 2 in innate and adaptive immune responses.
RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems.
Innate and adaptive immune responses contribute to host defence against pathogens. Innate immunity acts through Toll-like receptors (TLRs) and adaptive immunity acts through antigen-specific receptors. These papers show, by genetic targeting, that the caspase-recruitment domain (CARD)-containing serine/threonine kinase Rip2 (also known as RICK and CARDIAK) transduces signals for both the innate and adaptive immune systems. Rip2 -/- mice had defective immune responses downstream of TLRs and Nod proteins (molecules that are also implicated in the innate response), as well as impaired differentiation, cytokine production, activation and proliferation of T-helper 1 cells.
Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukaemia.
Chronic myelogenous leukaemia (CML) is caused by the BCR–ABL kinase. Imatinib mesylate (Gleevec), a selective inhibitor of this kinase, was approved for the treatment of CML in 2001. Kantarjian et al. assessed the effects of Gleevec in patients with late–chronic-phase CML in whom therapy with interferon-
Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication.
Prostaglandins such as PGE2 elicit a wide range of physiological responses. Zhu et al. show that levels of cyclooxygenase 2 (COX2), a key enzyme in the pathway that synthesizes PGE2, are markedly increased in human cells after infection with human cytomegalovirus (HCMV). Treatment of cells with a selective COX2 inhibitor reduced the production of infectious virus by a factor of 100, and virus replication was substantially restored when drug-blocked cultures were supplemented with PGE2. These findings indicate that induction of COX2 and synthesis of PGE2 are essential for efficient HCMV replication in human cells.
Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI.
Integrin-mediated cell adhesion is required to translocate the small GTPase Rac to the plasma membrane, where it can interact with its effectors. In this study, the authors used fluorescence resonance energy transfer to show that Rac only interacts with its effectors at specific regions at the edges of cells. This was due to the ability of integrins to target Rac to these regions and to dissociate it from RhocircleGDI, which binds to cytoplasmic Rac and blocks effector binding.
Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity.
Like ubiquitylation, sumoylation requires an E1-activating enzyme and an E2-type conjugating enzyme, Ubc9. Until now, Ubc9 was also thought to be sufficient for substrate recognition, which, in the case of ubiquitylation, is carried out by E3 ligases. Now, however, Schmidt and Müller report that protein inhibitor of activated STAT (PIAS) proteins can function as specific SUMO ligases, in a similar manner to E3 ubiquitin ligases, and can mediate the sumoylation of p53 and c-Jun. PIAS-mediated sumoylation of p53 markedly repressed p53's transcriptional activity, indicating a role for the PIAS–SUMO pathway in transcriptional regulation.
Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors.
The endophilin–CIN85–Cbl complex mediates ligand-dependent downregulation of c-Met.
The adaptor protein Cbl is involved in downregulating receptor-tyrosine kinases in response to ligand-induced activation by binding, through its Src-homology-2 (SH2) domain, to phosphorylated tyrosine residues. It then targets the receptors for ubiquitylation and subsequent degradation in lysosomes. But two new studies in Nature now show that Cbl also has a regulatory role in receptor internalization that is functionally separable from its ubiquitylation activity. Both research groups found that Cbl interacts, through its carboxyl terminus, with a complex that consists of endophilins — components of clathrin-coated vesicles that mediate endocytosis — and Cbl-interacting protein of 85 kDa, CIN85. The model proposed is that endophilin can alter the shape of the plasma membrane, thereby promoting membrane invagination, and that CIN85, an adaptor protein, might regulate receptor transport. | | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
7 nicotinic receptor.
.
90% of patients.
