Physical and functional interaction of filamin (actin-binding protein-280)and tumor necrosis factor receptor-associated factor 2

Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an intr acellular protein involved in signal transduction from TNF receptor I and I I and related receptors. TRAF2 is required for TNF-induced activation of c- Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and TRAF2 can also mediate activation of NF-kappa B. Here we have identified the act in-binding protein Filamin (actin-binding protein-280) as a TRAF2-interacti ng protein. Filamin binds to the Ring zinc finger domain of TRAF2, Overexpr essed Filamin inhibits TRAF2-induced activation of JNI/SAPK and of NF-kappa B. Furthermore, ectopically expressed Filamin inhibits NF-kappa B activati on induced via TNF, interleukin-1, Toll receptors, and TRAF6 but not activa tion induced via overexpression of NIK, a downstream effector in these path ways. Importantly, TNF fails to activate SAPK or NF-kappa B in a human mela noma cell line deficient in Filamin. Reintroduction of Filamin into these c ells restores the TNF response. The data imply a role for Filamin in inflam matory signal transduction pathways.