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In brief: May 2003

Apoptosis

Fas-associated death domain protein interacts with methyl-CpG binding protein 4: a potential link between genome surveillance and apoptosis
Screaton, R. A. et al.
Proc. Natl Acad. Sci. USA 100, 5211–5216 (2003) (DOI: 10.1073/pnas.0431215100) | Article | PubMed |

Fas-associated death domain protein (FADD) has been assumed to localize predominantly in the cytoplasm. The authors of this paper, though, report the primarily nuclear localization of FADD. Phosphorylation of FADD serine 194 was important for this localization and for interaction with a nucleocytoplasmic shuttling protein. FADD also interacted with methyl-CpG binding domain protein 4 (MBD4), a genome surveillance/DNA repair protein that was recently implicated in apoptosis regulation. So, FADD might have a new function in a new location.

Cell Death And Immunity

Cell death induced by granzyme C
Johnson, H. et al.
Blood 101, 3093–3101 (2003) | Article | PubMed |

Although much is known about the functions of granzymes A and B, granzyme C has been less well studied. Here, Johnson et al. show that mouse granzyme C (which is closely related to human granzyme H) causes cell death with similar kinetics to granzyme B and is of equal potency. Cell death that is induced by granzyme C requires its protease activity, results in externalization of phosphatidylserine, nuclear condensation and single-stranded but not double-stranded DNA nicking. Granzyme C causes swelling and depolarization of mitochondria, and death induced by this granzyme does not involve caspase activation, cleavage of BID (BH3-interacting domain death agonist) or activation of the CAD nuclease.

T-Cell Memory

CD4⁺ T cells are required for secondary expansion and memory in CD8⁺ T lymphocytes
Janssen, E. M. et al.
Nature 421, 852–856 (2003) | Article | PubMed |

Requirement for CD4⁺ T-cell help in generating functional CD8⁺ T-cell memory
Shedlock, D. J. & Shen, H.
Science 300, 337–339 (2003) | Article | PubMed |

Defective CD8⁺ T-cell memory following acute infection without CD4⁺ T-cell help
Sun, J. C. & Bevan, M. J.
Science 300, 339–342 (2003) | Article | PubMed |

Understanding how memory responses are generated is crucial if we are to develop improved vaccine strategies. Three recent papers have addressed the issue of whether T-cell help is required for the generation of functional CD8⁺ memory T cells. For primary CD8⁺ T-cell responses to certain antigens, CD4⁺ T cells are required to 'license' antigen-presenting cells (APCs) — thought to be mediated by CD40 signalling — to generate a response. But primary CD8⁺ T-cell responses to infectious agents do not often require T-cell help, because microbial products provide their own immunostimulatory signals for the direct activation of APCs. These studies now show that CD4⁺ T-cell help is necessary during the priming phase, but not during the recall response itself, to generate an effective CD8⁺ memory T-cell response.

T-Cell Activation

ISKAP-55 regulates integrin adhesion and formation of T cell–APC conjugates
Wang, H. et al.
Nature Immunol. 4, 366–374 (2003) | Article |

A function for the T-cell adaptor protein SKAP55 has long been sought. An initial clue to its role came from previous observations that SKAP55 binds to another T-cell adaptor ADAP, a regulator of integrin clustering. This study shows that similar to APAP, increased expression of SKAP55 in cell lines or primary mouse T cells potently upregulates the formation of T-cell-APC (antigen-presenting cell) conjugates in vitro. It seems that SKAP55 mediates this effect by upregulating integrin clustering and adhesion. So, SKAP55 joins ADAP as a crucial component of the poorly understood 'inside out' signalling pathway that regulates conjugate formation.

Epigenetics

Effects of tethering HP1 to euchromatic regions of the Drosophila genome
Li, Y. et al.
Development 130, 1817–1824 (2003) | Article | PubMed |

Heterochromatin protein 1 (HP1) is a non-histone chromosomal protein. Li et al. found that, when tethered to euchromatic sites, HP1 silenced nearby reporters. HP1 has been shown to interact with the methylated lysine 9 of histone 3 at centric regions, but in this system, the methylation requirement might be bypassed because silencing is not dependent on the dosage of the histone methyltransferase SU(VAR)3-9.

Anticancer Drugs

Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer
Watkins, D. N. et al.
Nature 422, 313–316 (2003) | Article | PubMed |

Small-cell lung cancer (SCLC) is highly aggressive and has very limited treatment options. Watkins et al. show that activation of the Hedgehog pathway, which has a well-characterized role in development, is involved in some types of SCLC, and that blockade of this pathway could be a novel therapeutic strategy.

Anticancer Drugs

A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome
Cools, J. et al.
N. Engl J. Med. 348, 1201–1214 (2003) | Article | PubMed |

Hypereosinophilic syndrome (HES) is a fatal blood disease that is characterized by an increase in inflammatory white blood cells. Cools et al. evaluated imatinib (Gleevec/Glivec; Novartis) in eleven patients with HES, nine of which had positive responses, and found evidence that the activity of imatinib could be due to inhibition of a tyrosine kinase produced by the fusion of the PDGFRA and FIPL1 genes.