CIN85 associates with TNF receptor 1 via Src and modulates TNF-alpha-induced apoptosis.
CIN85 is a multidomain protein that associates with receptors carrying tyrosine kinase domains. Here we report that it is also a component of the signaling complex associated with tumor necrosis factor receptor 1 (TNFR1), which lacks a tyrosine kinase domain. This was established by showing that CIN85 was co-precipitated with TNFR1, TRADD, cIAP-1 and TARF1/2, but not with FADD, RIP, caspase-8 or TRAF6. However, CIN85 did not bind directly to the cytoplasmic domain of TNFR1 (TNFR1-CYT) but to Src family kinases, Cbl and the p85alpha subunit of phosphatidylinositol 3-kinase (PI3-K p85alpha). Src bound directly to TNFR1-CYT, but Cbl and PI3-K p85alpha did not. A human cell line ectopically expressing CIN85 was 10 times more susceptible to TNF-alpha-induced apoptosis than control cells, which expressed identical levels of TNFR1 on their surface. However, the susceptibility of these two cell lines to CD95-induced apoptosis was the same. The three SH3 domains of CIN85 were essential for this increased susceptibility to apoptosis and its proline-rich regions were also required for maximal effect. TNF-alpha treatment recruited CIN85 to the TNFR1 signaling complex. Taken together, these results indicate that CIN85 associates with TNFR1 via Src and modulates TNF-alpha-induced apoptosis.
Narita
Tadashi
T
Laboratory of Bacterial Infection and Immunity, Department of Immunology, National Institute of Infectious Diseases, 1-23-1, Toyama, Tokyo 162-8640, Japan.
Nishimura
Tadahiro
T
Yoshizaki
Kazuyuki
K
Taniyama
Tadayoshi
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D006801:Humans; D009154:Mutation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; C433810:SH3KBP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases