Tumor Necrosis Factor Receptor 2 Signaling Induces Selective c-IAP1-dependent ASK1 Ubiquitination and Terminates Mitogen-activated Protein Kinase Signaling

TRAF2 and ASK1 play essential roles in tumor necrosis factor α (TNF-α)-induced mitogen-activated protein kinase signaling. Stimulation through TNF receptor 2 (TNFR2) leads to TRAF2 ubiquitination and subsequent proteasomal degradation. Here we show that TNFR2 signaling also leads to selective ASK1 ubiquitination and degradation in proteasomes. c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination, and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2-induced TRAF2 and ASK1 degradation. Moreover, in the absence of c-IAP1 TNFR2-mediated p38 and JNK activation was prolonged. Thus, the ubiquitin protein ligase activity of c-IAP1 is responsible for regulating the duration of TNF signaling in primary cells expressing TNFR2. TRAF2 and ASK1 play essential roles in tumor necrosis factor α (TNF-α)-induced mitogen-activated protein kinase signaling. Stimulation through TNF receptor 2 (TNFR2) leads to TRAF2 ubiquitination and subsequent proteasomal degradation. Here we show that TNFR2 signaling also leads to selective ASK1 ubiquitination and degradation in proteasomes. c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination, and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2-induced TRAF2 and ASK1 degradation. Moreover, in the absence of c-IAP1 TNFR2-mediated p38 and JNK activation was prolonged. Thus, the ubiquitin protein ligase activity of c-IAP1 is responsible for regulating the duration of TNF signaling in primary cells expressing TNFR2. Tumor necrosis factor α (TNF), 2The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; MAPKKK, mitogen-activated protein kinase kinase kinase; JNK, c-Jun N-terminal kinase; NIK, NF-κB-inducing kinase; GCKR, germinal center kinase-related; GST, glutathione S-transferase; IVT, in vitro translated; HA, hemagglutinin; E3, ubiquitin protein ligase; c-IAP1, cellular inhibitor of apoptosis protein-1; TRAF, TNFR-associated factor. 2The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; MAPKKK, mitogen-activated protein kinase kinase kinase; JNK, c-Jun N-terminal kinase; NIK, NF-κB-inducing kinase; GCKR, germinal center kinase-related; GST, glutathione S-transferase; IVT, in vitro translated; HA, hemagglutinin; E3, ubiquitin protein ligase; c-IAP1, cellular inhibitor of apoptosis protein-1; TRAF, TNFR-associated factor. a key mediator of the inflammatory response, functions by increasing the expression of a variety of effector molecules such as interleukin-1, interleukin-6, and Interferon-γ (1Tracey K.J. Cerami A. Annu. Rev. Med. 1994; 45: 491-503Crossref PubMed Scopus (947) Google Scholar). TNF binds to two distinct transmembrane receptors, TNF receptor 1 (TNFR1; p55) and TNF receptor 2 (TNFR2; p75). TNFR1 is ubiquitously expressed, whereas TNFR2 is found primarily on cells of the immune system and is highly regulated (2Wajant H. Pfizenmaier K. PubMed Scopus Google Scholar). TNFR1 is the of receptor and functions signaling for apoptosis of and of and inflammatory of TNFR2 in is TNFR2 and expression of TNFR2 in PubMed Scopus Google PubMed Google and in TNFR1 TNFR2 to and highly to H. A. H. PubMed Scopus Google K. K. 1994; PubMed Scopus Google to TNFR1 and TNFR2 signaling and play roles in H. PubMed Scopus Google Scholar). TRAF2 in is a key in the to activation of the mitogen-activated protein p38 and JNK H. PubMed Scopus Google Scholar). of the kinase of p38 and JNK, with TRAF2 TNF H. K. H. K. H. PubMed Scopus Google Scholar). the duration of p38 and JNK activation in to TNF is in K. A. H. K. K. K. H. PubMed Scopus Google Scholar). such as NF-κB-inducing kinase PubMed Scopus Google and germinal center A. Google also in the of signaling in to TNF, is cellular inhibitor of apoptosis 1 and 2 and also to signaling through with TRAF2 PubMed Scopus Google Scholar). to PubMed Scopus Google c-IAP1 and ubiquitin protein ligase by PubMed Scopus Google H. PubMed Google Scholar). c-IAP1, in found to play in TNF by of TNFR2 and the ubiquitination and subsequent degradation of TRAF2 PubMed Scopus Google Scholar). that TRAF2 is and JNK is in we also of ubiquitination and degradation. Here we show that GCKR, is in and B cells in a on the activity of absence of in B cells in to kinase and used for and and and JNK and used for and and used for used used and and used for H. K. K. K. PubMed Scopus Google of PubMed Scopus Google and of and in PubMed Scopus Google Scholar). and cells from cells with TNFR2 a from PubMed Google Scholar). cells with TNFR2 PubMed Scopus Google Scholar). cells with TNFR2 by H. Google cells on a and with the expression the cells and in 1 1 and with inhibitor and vitro protein PubMed Scopus Google Scholar). the protein and with in vitro ASK1 for 2 the by in and by by vitro ubiquitination by 1 of ASK1 in of 1 2 and 2 in the of c-IAP1 1 and of ubiquitin for 1 the with and by by B from PubMed Scopus Google by through a the PubMed Scopus Google Scholar). B cells by the B B cells in and cells in a 1 and in the of and for with protein for 1 and by with the for 1 on protein and the with and for in and on by the GCKR, and that c-IAP1 TRAF2 ubiquitination and is of JNK activation in cells expressing TNFR2 PubMed Scopus Google Scholar). NIK, and of p38 and JNK H. K. H. K. H. PubMed Scopus Google PubMed Scopus Google A. Google Scholar). that TRAF2 is in cells expressing we NIK, also to degradation TNFR2 cells that TNFR1 and TNFR2 PubMed Google with TNF for NIK, and with TNF in a in TRAF2 expression of GCKR, also in to TNFR2 signaling is required for ASK1 in cells and cells with TNF the the of ASK1 was by TNF in the of ASK1 in cells was by that was degradation with cells expressing TNFR2 and as with of TNFR2 ASK1 degradation of ASK1 that is a for TNFR2 is the cells with TNF in the of of the by to of and in and ASK1 was and to with in ASK1 TNF that ASK1 is a for and subsequent proteasomal ASK1 cells with TNF in the of for cells in and in the of and to ASK1 was the by and ASK1 was by with ASK1 by the with GCKR, and is a ubiquitin protein ligase that TRAF2 with TNF PubMed Scopus Google Scholar). c-IAP1 was responsible for ASK1 ubiquitination, cells with expression ASK1 and c-IAP1 c-IAP1 that in the the cells and the of the by of c-IAP1, c-IAP1 the of ASK1 TRAF2 also as a ubiquitin protein ligase PubMed Scopus Google we the that responsible for ASK1 cells with expression ASK1 and c-IAP1 the cells and of ASK1 was of c-IAP1, ASK1 that c-IAP1 is the for by c-IAP1, c-IAP1 was in cells with NIK, the cells and protein of c-IAP1 the of TRAF2 and Thus, TRAF2 and and to c-IAP1 in GCKR, ubiquitination and degradation. cells with expression in the the cells and the of ASK1 and c-IAP1 was by with and was used as cells with expression in the ASK1 and c-IAP1 by of TRAF2 with cells with expression in the the by for the cells with expression the cells with for and with ASK1 and TRAF2 by the of ASK1 and TRAF2 cells with TNF and ASK1 and TRAF2 of as as and by by that to with ASK1 and in c-IAP1 and with with with with ASK1 ASK1 was by c-IAP1 in vitro in as by a in the of protein of c-IAP1 that activity on show that c-IAP1 and binds ASK1 and ubiquitination in ASK1 with with and the was by in vitro ubiquitination was with the and the was by of ASK1 and TRAF2 in B and the of cells from with of the of is a of is a of the of c-IAP1 to and degradation PubMed Scopus Google Scholar). c-IAP1, to TRAF2 PubMed Scopus Google cells from animals a for the that c-IAP1 is the effector of TRAF2 and ASK1 ubiquitination of TNFR2 signaling. B cells and the on and B cells Rev. PubMed Scopus Google Scholar). and B cells from and with for the of TRAF2 and ASK1 through TNFR2 a in TRAF2 that was by the inhibitor and in with by the in cells PubMed Scopus Google TRAF2 expression was by TNFR2 signaling in the absence of of ASK1 protein in cells signaling TNFR1 on ASK1 ASK1 was in B cells c-IAP1 a of TNFR2 in the of of of TNFR2-induced TRAF2 and ASK1 degradation and p38 and JNK kinase signaling. B cells from and with with for cells in and TRAF2 and by B cells from and with for ASK1 and by B cells from and with for the p38 and p38 by B cells from and as in and by p38 and JNK in B that activation of the of TNFR2 on the expression of we the activation of p38 and JNK in and B p38 and JNK by as a of PubMed Scopus Google K. PubMed Scopus Google Scholar). ASK1 is required for the of p38 and JNK and the duration of p38 and JNK is in K. A. H. K. K. K. H. PubMed Scopus Google Scholar). B cells with the p38 and JNK and and p38 and JNK in B cells to the in p38 and JNK for in B of TRAF2 and ASK1 is a for the duration of p38 and JNK activation in primary B is was found to apoptosis in cells H. K. K. K. PubMed Scopus Google Scholar). is kinase that is responsible for activation of in 1 A. K. PubMed Scopus Google H. K. H. H. PubMed Scopus Google and cells H. K. K. K. PubMed Scopus Google K. K. K. H. PubMed Scopus Google Scholar). ASK1 in the JNK and p38 signaling by and H. K. H. K. H. PubMed Scopus Google Scholar). ASK1 is in to and such as and signaling through such as and A. K. H. PubMed Scopus Google Scholar). of TRAF2 and in the of TNF ASK1 and TRAF2 is essential for activation of the H. K. H. K. H. PubMed Scopus Google Scholar). of TRAF2 to ASK1 the N-terminal of the and the of the H. K. H. K. H. PubMed Scopus Google Scholar). TRAF2 and ASK1 and activation of JNK and p38 in to TNF and to K. A. H. K. K. K. H. PubMed Scopus Google Scholar). p38 and JNK activation and is of that c-IAP1 is responsible for the ubiquitination and subsequent degradation of TRAF2 and is that we that c-IAP1 is of TRAF2 and that in cells c-IAP1 TRAF2 PubMed Scopus Google Scholar). that the ubiquitin protein ligase is a key of TRAF2 expression and in cells with TNF H. A. PubMed Scopus Google Scholar). to a in signaling apoptosis in primary and cells PubMed Scopus Google Scholar). that degradation of TRAF2 is in primary B cells that is in a of TRAF2 c-IAP1 binds TRAF2 PubMed Scopus Google and TRAF2 and ASK1 to H. K. H. K. H. PubMed Scopus Google that TRAF2 as a c-IAP1 and a for the of and also with TRAF2 in the TNF expression was by c-IAP1 by that in a TRAF2 and c-IAP1 is to ubiquitination and that c-IAP1 for for in the that c-IAP1 binds and TRAF2 in vitro TRAF2 PubMed Scopus Google Scholar). Moreover, binds TRAF2 in vitro highly selective of the is by the that expression is highly in cells PubMed Scopus Google for c-IAP1 for the TNFR2-induced ubiquitination of TRAF2 and of signaling activation is a key for the of cellular by such as protein degradation. receptors, receptor and and by and degradation PubMed Scopus Google Scholar). the cellular protein degradation to signaling as the is by and a variety of such molecules in the and protein signaling for degradation PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). the c-IAP1 as a of signaling of TNFR2. activation in TRAF2 and ASK1 as ubiquitination and subsequent of of kinase signaling in the TNF the that TNFR2 in inflammatory Pfizenmaier K. Google PubMed Scopus Google PubMed Scopus Google a to by TNFR1 Tumor necrosis factor α (TNF), 2The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; MAPKKK, mitogen-activated protein kinase kinase kinase; JNK, c-Jun N-terminal kinase; NIK, NF-κB-inducing kinase; GCKR, germinal center kinase-related; GST, glutathione S-transferase; IVT, in vitro translated; HA, hemagglutinin; E3, ubiquitin protein ligase; c-IAP1, cellular inhibitor of apoptosis protein-1; TRAF, TNFR-associated factor. 2The abbreviations used are: TNF, tumor necrosis factor; TNFR, TNF receptor; MAPKKK, mitogen-activated protein kinase kinase kinase; JNK, c-Jun N-terminal kinase; NIK, NF-κB-inducing kinase; GCKR, germinal center kinase-related; GST, glutathione S-transferase; IVT, in vitro translated; HA, hemagglutinin; E3, ubiquitin protein ligase; c-IAP1, cellular inhibitor of apoptosis protein-1; TRAF, TNFR-associated factor. a key mediator of the inflammatory response, functions by increasing the expression of a variety of effector molecules such as interleukin-1, interleukin-6, and Interferon-γ (1Tracey K.J. Cerami A. Annu. Rev. Med. 1994; 45: 491-503Crossref PubMed Scopus (947) Google Scholar). TNF binds to two distinct transmembrane receptors, TNF receptor 1 (TNFR1; p55) and TNF receptor 2 (TNFR2; p75). TNFR1 is ubiquitously expressed, whereas TNFR2 is found primarily on cells of the immune system and is highly regulated (2Wajant H. Pfizenmaier K. PubMed Scopus Google Scholar). TNFR1 is the of receptor and functions signaling for apoptosis of and of and inflammatory of TNFR2 in is TNFR2 and expression of TNFR2 in PubMed Scopus Google PubMed Google and in TNFR1 TNFR2 to and highly to H. A. H. PubMed Scopus Google K. K. 1994; PubMed Scopus Google Scholar). TNFR-associated to TNFR1 and TNFR2 signaling and play roles in H. PubMed Scopus Google Scholar). TRAF2 in is a key in the to activation of the mitogen-activated protein p38 and JNK H. PubMed Scopus Google Scholar). of the kinase of p38 and JNK, with TRAF2 TNF H. K. H. K. H. PubMed Scopus Google Scholar). the duration of p38 and JNK activation in to TNF is in K. A. H. K. K. K. H. PubMed Scopus Google Scholar). such as NF-κB-inducing kinase PubMed Scopus Google and germinal center A. Google also in the of signaling in to TNF, is cellular inhibitor of apoptosis 1 and 2 and also to signaling through with TRAF2 PubMed Scopus Google Scholar). to PubMed Scopus Google c-IAP1 and ubiquitin protein ligase by PubMed Scopus Google H. PubMed Google Scholar). c-IAP1, in found to play in TNF by of TNFR2 and the ubiquitination and subsequent degradation of TRAF2 PubMed Scopus Google Scholar). that TRAF2 is and JNK is in we also of ubiquitination and degradation. Here we show that GCKR, is in and B cells in a on the activity of absence of in B cells in to kinase signaling. and used for and and and JNK and used for and and used for used used and and used for H. K. K. K. PubMed Scopus Google of PubMed Scopus Google and of and in PubMed Scopus Google Scholar). and cells from cells with TNFR2 a from PubMed Google Scholar). cells with TNFR2 PubMed Scopus Google Scholar). cells with TNFR2 by H. Google cells on a and with the expression the cells and in 1 1 and with inhibitor and vitro protein PubMed Scopus Google Scholar). the protein and with in vitro ASK1 for 2 the by in and by by vitro ubiquitination by 1 of ASK1 in of 1 2 and 2 in the of c-IAP1 1 and of ubiquitin for 1 the with and by by B from PubMed Scopus Google by through a the PubMed Scopus Google Scholar). B cells by the B B cells in and cells in a 1 and in the of and for with protein for 1 and by with the for 1 on protein and the with and for in and on by the and used for and and and JNK and used for and and used for used used and and used for H. K. K. K. PubMed Scopus Google of PubMed Scopus Google and of and in PubMed Scopus Google Scholar). and cells from cells with TNFR2 a from PubMed Google Scholar). cells with TNFR2 PubMed Scopus Google Scholar). cells with TNFR2 by H. Google Scholar). cells on a and with the expression the cells and in 1 1 and with inhibitor and vitro protein PubMed Scopus Google Scholar). the protein and with in vitro ASK1 for 2 the by in and by by vitro ubiquitination by 1 of ASK1 in of 1 2 and 2 in the of c-IAP1 1 and of ubiquitin for 1 the with and by by B from PubMed Scopus Google by through a the PubMed Scopus Google Scholar). B cells by the B B cells in and cells in a 1 and in the of and for with protein for 1 and by with the for 1 on protein and the with and for in and on by the GCKR, and that c-IAP1 TRAF2 ubiquitination and is of JNK activation in cells expressing TNFR2 PubMed Scopus Google Scholar). NIK, and of p38 and JNK H. K. H. K. H. PubMed Scopus Google PubMed Scopus Google A. Google Scholar). that TRAF2 is in cells expressing we NIK, also to degradation TNFR2 cells that TNFR1 and TNFR2 PubMed Google with TNF for NIK, and with TNF in a in TRAF2 expression of GCKR, also in to TNFR2 signaling is required for ASK1 in cells and cells with TNF the the of ASK1 was by TNF in the of ASK1 in cells was by that was degradation with cells expressing TNFR2 and as with of TNFR2 ASK1 degradation of ASK1 that is a for TNFR2 is the cells with TNF in the of of the by to of and in and ASK1 was and to with in ASK1 TNF that ASK1 is a for and subsequent proteasomal GCKR, and is a ubiquitin protein ligase that TRAF2 with TNF PubMed Scopus Google Scholar). c-IAP1 was responsible for ASK1 ubiquitination, cells with expression ASK1 and c-IAP1 c-IAP1 that in the the cells and the of the by of c-IAP1, c-IAP1 the of ASK1 TRAF2 also as a ubiquitin protein ligase PubMed Scopus Google we the that responsible for ASK1 cells with expression ASK1 and c-IAP1 the cells and of ASK1 was of c-IAP1, ASK1 that c-IAP1 is the for by c-IAP1, c-IAP1 was in cells with NIK, the cells and protein of c-IAP1 the of TRAF2 and Thus, TRAF2 and and to c-IAP1 in GCKR, ubiquitination and degradation. cells with expression in the the cells and the of ASK1 and c-IAP1 was by with and was used as cells with expression in the ASK1 and c-IAP1 by of TRAF2 with cells with expression in the the by for the cells with expression the cells with for and with ASK1 and TRAF2 by the of ASK1 and TRAF2 cells with TNF and ASK1 and TRAF2 of as as and by by that to with ASK1 and in c-IAP1 and with with with with ASK1 ASK1 was by c-IAP1 in vitro in as by a in the of protein of c-IAP1 that activity on show that c-IAP1 and binds ASK1 and ubiquitination in ASK1 with with and the was by in vitro ubiquitination was with the and the was by of ASK1 and TRAF2 in B and the of cells from with of the of is a of is a of the of c-IAP1 to and degradation PubMed Scopus Google Scholar). c-IAP1, to TRAF2 PubMed Scopus Google cells from animals a for the that c-IAP1 is the effector of TRAF2 and ASK1 ubiquitination of TNFR2 signaling. B cells and the on and B cells Rev. PubMed Scopus Google Scholar). and B cells from and with for the of TRAF2 and ASK1 through TNFR2 a in TRAF2 that was by the inhibitor and in with by the in cells PubMed Scopus Google TRAF2 expression was by TNFR2 signaling in the absence of of ASK1 protein in cells signaling TNFR1 on ASK1 ASK1 was in B cells c-IAP1 a of TNFR2 in the of of of TNFR2-induced TRAF2 and ASK1 degradation and p38 and JNK kinase signaling. B cells from and with with for cells in and TRAF2 and by B cells from and with for ASK1 and by B cells from and with for the p38 and p38 by B cells from and as in and by p38 and JNK in B that activation of the of TNFR2 on the expression of we the activation of p38 and JNK in and B p38 and JNK by as a of PubMed Scopus Google K. PubMed Scopus Google Scholar). ASK1 is required for the of p38 and JNK and the duration of p38 and JNK is in K. A. H. K. K. K. H. PubMed Scopus Google Scholar). B cells with the p38 and JNK and and p38 and JNK in B cells to the in p38 and JNK for in B of TRAF2 and ASK1 is a for the duration of p38 and JNK activation in primary B TNF GCKR, and that c-IAP1 TRAF2 ubiquitination and is of JNK activation in cells expressing TNFR2 PubMed Scopus Google Scholar). NIK, and of p38 and JNK H. K. H. K. H. PubMed Scopus Google PubMed Scopus Google A. Google Scholar). that TRAF2 is in cells expressing we NIK, also to degradation TNFR2 cells that TNFR1 and TNFR2 PubMed Google with TNF for NIK, and with TNF in a in TRAF2 expression of GCKR, also in to TNFR2 signaling is required for ASK1 in cells and cells with TNF the the of ASK1 was by TNF in the of ASK1 in cells was by that was degradation with cells expressing TNFR2 and as with of TNFR2 ASK1 degradation. degradation of ASK1 that is a for TNFR2 is the cells with TNF in the of of the by to of and in and ASK1 was and to with in ASK1 TNF that ASK1 is a for and subsequent proteasomal degradation. c-IAP1 GCKR, and is a ubiquitin protein ligase that TRAF2 with TNF PubMed Scopus Google Scholar). c-IAP1 was responsible for ASK1 ubiquitination, cells with expression ASK1 and c-IAP1 c-IAP1 that in the the cells and the of the by of c-IAP1, c-IAP1 the of ASK1 TRAF2 also as a ubiquitin protein ligase PubMed Scopus Google we the that responsible for ASK1 cells with expression ASK1 and c-IAP1 the cells and of ASK1 was of c-IAP1, ASK1 that c-IAP1 is the for by c-IAP1, c-IAP1 was in cells with NIK, the cells and protein of c-IAP1 the of TRAF2 and Thus, TRAF2 and and to c-IAP1 in the of ASK1 and TRAF2 cells with TNF and ASK1 and TRAF2 of as as and by by that to degradation. c-IAP1 with ASK1 and in c-IAP1 and with with with with ASK1 ASK1 was by c-IAP1 in vitro in as by a in the of protein of c-IAP1 that activity on show that c-IAP1 and of ASK1 and TRAF2 in B and the of cells from with of the of is a of is a of the of c-IAP1 to and degradation PubMed Scopus Google Scholar). c-IAP1, to TRAF2 PubMed Scopus Google cells from animals a for the that c-IAP1 is the effector of TRAF2 and ASK1 ubiquitination of TNFR2 signaling. B cells and the on and B cells Rev. PubMed Scopus Google Scholar). and B cells from and with for the of TRAF2 and ASK1 through TNFR2 a in TRAF2 that was by the inhibitor and in with by the in cells PubMed Scopus Google TRAF2 expression was by TNFR2 signaling in the absence of of ASK1 protein in cells signaling TNFR1 on ASK1 ASK1 was in B cells c-IAP1 a of TNFR2 in the of of of signaling. p38 and JNK in B that activation of the of TNFR2 on the expression of we the activation of p38 and JNK in and B p38 and JNK by as a of PubMed Scopus Google K. PubMed Scopus Google Scholar). ASK1 is required for the of p38 and JNK and the duration of p38 and JNK is in K. A. H. K. K. K. H. PubMed Scopus Google Scholar). B cells with the p38 and JNK and and p38 and JNK in B cells to the in p38 and JNK for in B of TRAF2 and ASK1 is a for the duration of p38 and JNK activation in primary B is was found to apoptosis in cells H. K. K. K. PubMed Scopus Google Scholar). is kinase that is responsible for activation of in 1 A. K. PubMed Scopus Google H. K. H. H. PubMed Scopus Google and cells H. K. K. K. PubMed Scopus Google K. K. K. H. PubMed Scopus Google Scholar). ASK1 in the JNK and p38 signaling by and H. K. H. K. H. PubMed Scopus Google Scholar). ASK1 is in to and such as and signaling through such as and A. K. H. PubMed Scopus Google Scholar). of TRAF2 and in the of TNF ASK1 and TRAF2 is essential for activation of the H. K. H. K. H. PubMed Scopus Google Scholar). of TRAF2 to ASK1 the N-terminal of the and the of the H. K. H. K. H. PubMed Scopus Google Scholar). TRAF2 and ASK1 and activation of JNK and p38 in to TNF and to K. A. H. K. K. K. H. PubMed Scopus Google Scholar). p38 and JNK activation and is of that c-IAP1 is responsible for the ubiquitination and subsequent degradation of TRAF2 and is that we that c-IAP1 is of TRAF2 and that in cells c-IAP1 TRAF2 PubMed Scopus Google Scholar). that the ubiquitin protein ligase is a key of TRAF2 expression and in cells with TNF H. A. PubMed Scopus Google Scholar). to a in signaling apoptosis in primary and cells PubMed Scopus Google Scholar). that degradation of TRAF2 is in primary B cells that is in a of TRAF2 c-IAP1 binds TRAF2 PubMed Scopus Google and TRAF2 and ASK1 to H. K. H. K. H. PubMed Scopus Google that TRAF2 as a c-IAP1 and a for the of and also with TRAF2 in the TNF expression was by c-IAP1 by that in a TRAF2 and c-IAP1 is to ubiquitination and that c-IAP1 for for in the that c-IAP1 binds and TRAF2 in vitro TRAF2 PubMed Scopus Google Scholar). Moreover, binds TRAF2 in vitro highly selective of the is by the that expression is highly in cells PubMed Scopus Google for c-IAP1 for the TNFR2-induced ubiquitination of TRAF2 and of signaling activation is a key for the of cellular by such as protein degradation. receptors, receptor and and by and degradation PubMed Scopus Google Scholar). the cellular protein degradation to signaling as the is by and a variety of such molecules in the and protein signaling for degradation PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). the c-IAP1 as a of signaling of TNFR2. activation in TRAF2 and ASK1 as ubiquitination and subsequent of of kinase signaling in the TNF the that TNFR2 in inflammatory Pfizenmaier K. Google PubMed Scopus Google PubMed Scopus Google a to by TNFR1 ASK1 is was found to apoptosis in cells H. K. K. K. PubMed Scopus Google Scholar). is kinase that is responsible for activation of in 1 A. K. PubMed Scopus Google H. K. H. H. PubMed Scopus Google and cells H. K. K. K. PubMed Scopus Google K. K. K. H. PubMed Scopus Google Scholar). ASK1 in the JNK and p38 signaling by and H. K. H. K. H. PubMed Scopus Google Scholar). ASK1 is in to and such as and signaling through such as and A. K. H. PubMed Scopus Google Scholar). of TRAF2 and in the of TNF ASK1 and TRAF2 is essential for activation of the H. K. H. K. H. PubMed Scopus Google Scholar). of TRAF2 to ASK1 the N-terminal of the and the of the H. K. H. K. H. PubMed Scopus Google Scholar). TRAF2 and ASK1 and activation of JNK and p38 in to TNF and to K. A. H. K. K. K. H. PubMed Scopus Google Scholar). p38 and JNK activation and is of that c-IAP1 is responsible for the ubiquitination and subsequent degradation of TRAF2 and is that we that c-IAP1 is of TRAF2 and that in cells c-IAP1 TRAF2 PubMed Scopus Google Scholar). that the ubiquitin protein ligase is a key of TRAF2 expression and in cells with TNF H. A. PubMed Scopus Google Scholar). to a in signaling apoptosis in primary and cells PubMed Scopus Google Scholar). that degradation of TRAF2 is in primary B cells that is in a of TRAF2 c-IAP1 binds TRAF2 PubMed Scopus Google and TRAF2 and ASK1 to H. K. H. K. H. PubMed Scopus Google that TRAF2 as a c-IAP1 and a for the of and also with TRAF2 in the TNF expression was by c-IAP1 by that in a TRAF2 and c-IAP1 is to ubiquitination and that c-IAP1 for for in the that c-IAP1 binds and TRAF2 in vitro TRAF2 PubMed Scopus Google Scholar). Moreover, binds TRAF2 in vitro highly selective of the is by the that expression is highly in cells PubMed Scopus Google for c-IAP1 for the TNFR2-induced ubiquitination of TRAF2 and of signaling activation is a key for the of cellular by such as protein degradation. receptors, receptor and and by and degradation PubMed Scopus Google Scholar). the cellular protein degradation to signaling as the is by and a variety of such molecules in the and protein signaling for degradation PubMed Scopus Google PubMed Scopus Google PubMed Scopus Google Scholar). the c-IAP1 as a of signaling of TNFR2. activation in TRAF2 and ASK1 as ubiquitination and subsequent of of kinase signaling in the TNF the that TNFR2 in inflammatory Pfizenmaier K. Google PubMed Scopus Google PubMed Scopus Google a to by TNFR1 of for the and and for and