Delivering the kiss of death

Trambas, Christina; Griffiths, Gillian M.

doi:10.1038/ni0503-399

Cited by 165 publications

(141 citation statements)

References 83 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…(28,44) The regulation of RANKL in osteoblastic cells is similar to that of FasL in cytotoxic Tlymphocytes; however, there are also some differences. (24,(46)(47)(48)(49) Both Rab27a and Rab27b are involved in stimulation-dependent RANKL release in osteoblastic cells (Figs. 1 and 2).…”

Section: Discussionmentioning

confidence: 99%

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Kariya

Honma

Hanamura

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

The quantity of the receptor activator of NF-kB ligand (RANKL) expressed at the cell surface of osteoblastic cells is an important factor regulating osteoclast activation. Previously, RANKL was found to be localized to secretory lysosomes in osteoblastic cells and to translocate to the cell surface in response to stimulation with RANK-Fc-conjugated beads. However, the in vivo significance of stimulation-dependent RANKL release has not been elucidated. In this study we show that small GTPases Rab27a and Rab27b are involved in the stimulation-dependent RANKL release pathway in osteoblastic cells. Suppression of either Rab27a or Rab27b resulted in a marked reduction in RANKL release after stimulation. Slp4-a, Slp5, and Munc13-4 acted as effector molecules that coordinated Rab27a/b activity in this pathway. Suppression of Rab27a/b or these effector molecules did not inhibit accumulation of RANKL in lysosomal vesicles around the stimulated sites but did inhibit the fusion of these vesicles to the plasma membrane. In osteoblastic cells, suppression of the effector molecules resulted in reduced osteoclastogenic ability. Furthermore, Jinx mice, which lack a functional Munc13-4 gene, exhibited a phenotype characterized by increased bone volume near the tibial metaphysis caused by low bone resorptive activity. In conclusion, stimulation-dependent RANKL release is mediated by Rab27a/b and their effector molecules, and this mechanism may be important for osteoclast activation in vivo. ß

show abstract

Section: Discussionmentioning

confidence: 99%

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Kariya

Honma

Hanamura

et al. 2010

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…3,9 The activation-induced movement of secretory lysosomes towards the cell surface and into the immunological synapse proceeds along the microtubules, whereas the last step to plasma membrane appears to be actin filament-dependent. 10 However, the exact signaling events initiated by the T cell receptor leading to the degranulation and cell surface expression of FasL are largely unknown. In particular, it is not clear to what extent T cell receptor-induced kinase pathways, as simulated by addition of phorbol ester, and increase in intracellular Ca 2 þ , simulated by calcium ionophor, contribute to this process.…”

Section: Fas (Cd95/apo-1) Ligand (Fasl) Is a Member Of The Tnf Familymentioning

confidence: 99%

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

et al. 2008

View full text Add to dashboard Cite

Fas (CD95/Apo-1) ligand is a potent inducer of apoptosis and one of the major killing effector mechanisms of cytotoxic T cells. Thus, Fas ligand activity has to be tightly regulated, involving various transcriptional and post-transcriptional processes. For example, preformed Fas ligand is stored in secretory lysosomes of activated T cells, and rapidly released by degranulation upon reactivation. In this study, we analyzed the minimal requirements for activation-induced degranulation of Fas ligand. T cell receptor activation can be mimicked by calcium ionophore and phorbol ester. Unexpectedly, we found that stimulation with phorbol ester alone is sufficient to trigger Fas ligand release, whereas calcium ionophore is neither sufficient nor necessary. The relevance of this process was confirmed in primary CD4 þ and CD8 þ T cells and NK cells. Although the activation of protein kinase(s) was absolutely required for Fas ligand degranulation, protein kinase C or A were not involved. Previous reports have shown that preformed Fas ligand co-localizes with other markers of cytolytic granules. We found, however, that the activationinduced degranulation of Fas ligand has distinct requirements and involves different mechanisms than those of the granule markers CD63 and CD107a/Lamp-1. We conclude that activation-induced degranulation of Fas ligand in cytotoxic lymphocytes is differently regulated than other classical cytotoxic granule proteins.

show abstract

“…17 Once activated, NK cells release granzymes and perforin to induce apoptosis of the target cells. [18][19][20] The graft-versus-leukemia (GvL) 21 effect mediated by donor-derived immune effectors early after hematopoietic stem cell transplantation (HSCT) may eradicate residual tumor cells and may be crucial in preventing disease relapse. Donor-derived NK cells typically undergo differentiation within 30 days 22 and might thus participate in an early GvL effect.…”

Section: Introductionmentioning

confidence: 99%

Early evaluation of natural killer activity in post-transplant acute myeloid leukemia patients

Pittari

Fregni

Roguet

et al. 2009

Bone Marrow Transplant

View full text Add to dashboard Cite

Delivering the kiss of death

Cited by 165 publications

References 83 publications

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells

Distinct requirements for activation-induced cell surface expression of preformed Fas/CD95 ligand and cytolytic granule markers in T cells

Early evaluation of natural killer activity in post-transplant acute myeloid leukemia patients

Contact Info

Product

Resources

About