Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is a Death Receptor for Granzyme B during Cytotoxic T Cell–Induced Apoptosis

Motyka, Bruce; Korbutt, Gregory S.; Pinkoski, Michael J.; Heibein, Jeffrey A.; Caputo, Annalisa; Hobman, Marita; Barry, Michèle; Shostak, Irene; Sawchuk, Tracy; Holmes, Charles F.B.; Gauldie, Jack; Bleackley, R. Chris

doi:10.1016/s0092-8674(00)00140-9

Cited by 353 publications

(335 citation statements)

References 61 publications

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“…42 Moreover, since granzyme B can directly enter target cells by a receptor, without the involvement of perforin, the cells can be induced to undergo apoptosis by both perforin-and FasL-independent pathways. 43 Another interesting observation was that, while caspase activation was only partially required to induce 39.5-B7 lysis by perforin-mediated cytotoxicity, perforin-independent CTL lysis of 39.5-B7 cells required caspase activation to transmit death signals to the cells. Malyguine et al 44 have reported that the caspase inhibitor zVAD-fmk had no or significantly lower effect on B6-Smn T-cells cytotoxicity against A20 cells.…”

Section: Discussionmentioning

confidence: 99%

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

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Perforin/granzyme B-and Fas/FasL-mediated killing pathways are the main effector mechanisms of CTL and NK cells in antitumor immune responses. In this study, we investigated the relative role of these two lytic mechanisms in protection of the host from tumor progression, as well as spontaneous metastasis, using the D122 Lewis lung carcinoma and its gene-modified cells. Utilizing perforin knockout mice (B6-PKO) and Fas and FasL mutant (B6-MRL and B6-Smn) mice, we found that perforin expression in the host plays a crucial function in the prevention of metastasis. However, local tumor rejection of an H-2K b and B7-1 transfectant, 39.5-B7 cells, was not dependent either on perforin or Fas/FasL expression in vivo. In addition, CTL lysis of 39.5-B7 cells was independent of perforin and Fas/FasL interactions in 18-hour in vitro assays. We also confirmed that CD8 T-cells were responsible for rejecting 39.5-B7 local tumors, yet cytokines, TNF-a and gIFN were not involved in tumor rejection in vivo. Furthermore, blocking assays using caspase inhibitors (zVAD-fmk, zIETD-fmk and zLEHD-fmk) showed that, whereas caspase activation was partially required to induce 39.5-B7 lysis mediated by the perforin-dependent pathway, 39.5-B7 lysis by CTLs through the perforin-independent mechanism required caspase activation. Thus, these results suggested that perforin, Fas/FasL, gIFN and TNF-a independent lytic mechanisms, mediated by CD8 T cells, have a crucial role in rejection of 39.5-B7 cells in vivo. Caspase activation is a pre requisite for apoptosis of targets by CTLs

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Section: Discussionmentioning

confidence: 99%

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

et al. 2004

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“…It is possible that the uptake of GB and/or trafficking of GB to the nucleolus could vary in the different cell types (30,31). Preliminary comparison of undifferentiated and differentiated AoSMCs in terms of their levels of expression of the cation-independent mannose-6-phosphate receptor by immunoblotting did not reveal increased levels of this receptor for GB in the differentiated cells (results not shown).…”

Section: Discussionmentioning

confidence: 99%

Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: Insights into the association of specific autoantibodies with distinct disease phenotypes

Ulanet¹,

Flavahan²,

Casciola‐Rosen³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate the association of specific autoantibodies with distinct disease phenotypes. The association of autoantibodies to nucleophosmin/ B23 with pulmonary hypertension in scleroderma, and the susceptibility of autoantigens to cleavage by granzyme B (GB), provided a focus for these studies.Methods. Intact cells were subjected to cytotoxic lymphocyte granule-induced death, and the susceptibility of autoantigens to cleavage by GB was addressed by immunoblotting and/or by a novel immunofluorescence assay.Results. B23 was cleaved efficiently by GB in vitro, but was highly resistant to cleavage by GB during cytotoxic lymphocyte granule-mediated death of many intact cell types. In contrast, this molecule was highly susceptible to GB-mediated proteolysis exclusively in differentiated vascular smooth muscle cells. Topoisomerase I and several other GB substrates did not show this striking change in cleavage susceptibility in different cell types.Conclusion. These data demonstrate that the cleavage of B23 by GB in intact cells is dependent upon both cell type and phenotype. The susceptibility of this autoantigen (which is associated with a distinct pulmonary vascular phenotype in scleroderma) to GBmediated proteolysis selectively in vascular smooth muscle cells suggests that the GB-cleavable conformation of autoantigens may occur selectively in the target tissue, and may play a role in shaping the phenotypespecific autoimmune response.

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“…It codes for a multifunctional receptor involved in intracellular lysosmal enzyme trafficking, TGF activation and IGF2 degradation. Granzyme B internalization by M6P/IGF2R is also required for cytotoxic T cells to induce apoptosis in cells targeted for death, leading to be referred as a 'death receptor' (Motyka et al, 2000). The M6P/IGF2R also plays a crucial role in regulating mammalian fetal growth and development (Filson et al, 1993).…”

Section: )mentioning

confidence: 99%

Genetics of hepatocellular tumors

2006

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Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1a (HNF1a) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/b-catenin pathway through CTNNB1/b-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently b-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.

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Mannose 6-Phosphate/Insulin-like Growth Factor II Receptor Is a Death Receptor for Granzyme B during Cytotoxic T Cell–Induced Apoptosis

Cited by 353 publications

References 61 publications

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL

Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: Insights into the association of specific autoantibodies with distinct disease phenotypes

Genetics of hepatocellular tumors

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